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iTffir'fV 


EXPERIMENTAL 


PHAKMACOLOGT 


BY 

HUGH  McGUIGAN,  Ph.D.,  M.D. 

PROFESSOR  OF  PHARMACOLOGY  IN  THE  UNIVERSITY    OF   ILLINOIS,    COLLEGE  OF 
MEDICINE,   CHICAGO,   ILLINOIS 


lIllustrateD  witb  56  ^Engravings  an&  7  ColoreO  iplates 


LEA    &    FEBIGER 

IMIILADELPHIA  AND  NEW   YORK 
1  0  M) 


>  iLfoZi 


Copyright 

LEA  &  FEBIGER 

1919 


PREFACE. 


Ix  the  preparation  of  this  manual  an  attempt  has  been  made 
to  present  experimental  pharmacology  in  a  brief,  concise  form, 
yet  to  give  the  student  an  adequate  view  of  the  field.  In  an 
elementary  course  where  time  is  limited,  it  is  neither  possible  nor 
necessary  that  each  student  or  group  of '  students  should  perform 
each  separate  experiment.  However,  every  student  should  endeavor 
to  see  the  work  of  all  the  others  and  be  able  to  discuss  these 
results,  since  a  knowledge  of  the  action  of  drugs  is  more  important 
for  the  majority  than  the  development  of  technical  skill.  On  the 
other  hand,  it  should  be  emphasized  that  the  performance  of  as 
many  experiments  as  possible  is  the  best  means  of  gaining  a  knowl- 
edge of  drug  action.  An  excellent  method  of  correlating  the 
student's  knowledge  is  to  compare  the  action  of  one  drug  with 
that  of  another.  It  is  advised,  therefore,  that  the  exercises  be 
studied  in  advance.  The  efi'ect  of  each  drug  studied  should  be 
compared  in  detail  with  those  of  the  preceding  ones;  especially 
should  those  drugs  that  are  closely  related,  such  as  eserin,  pilo- 
carpin,  strychnin,  caffein,  digitalis  and  epinephrin  be  studied 
together.  It  is  only  by  such  comparisons  that  a  knowledge  of  drug 
action  can  be  attained. 

Laboratory  work  in  pharmacology  has  as  its  aim  three  main 


1.  To  give  a  first-hand  knowledge  of  the  action  of  drugs,  and  to 
educate  the  student  in  the  i)roperties  of  living,  circulating  tissues. 
This  knowledge  can  be  obtained  in  no  other  way, 

2.  To  illustrate  the  practice  of  pharmacologic  investigations  and 
the  methods  of  procuring  records  and  tracings.  This  enables  the 
student  better  to  understand  literature  and  illustrations, 

3.  To  develop  the  technic  and  methods^  of  research,  and  the 
spirit  of  investigation. 

This  manual  attempts  to  follow  and  illustrate  the  most 
important  [jart  of  the  text-book  work.  Sufficient  exi)erimcnts  are 
given  U)  rlcmonstrate  the  chief  actions  of  each  drug.  Some  i)oints 
are  rluplicated,  but  since  each  student  does  not  perform   every 


iv  PREFACE 

exercise,  there  may  be  no  actual  repetition.  Variations  may  be 
made  as  desired  and  demonstrations  added.  Those  inchided  in 
this  outline  are  the  accumulation  of  several  years.  No  claim  to 
originality  is  made.  In  fact  an  effort  has  been  made  to  include 
those  exercises  which  have  been  standardized  by  long  and  general 
use.  In  many  instances  we  are  not  now  able  to  credit  the  method 
outlined  to  its  original  source.  Our  chief  attention  has  been 
devoted  to  selecting  those  of  instructional  value.  However,  in 
this  connection  it  affords  us  pleasure  to  acknowledge  our  obliga- 
tions to  such  eminent  authorities  as  Cushny,  Sollmann,  Greene, 
Stewart,  Jackson,  Becht,  Hatcher,  Hirschf elder,  Hoskins,  Dreyer 
and  others.  H.  McG. 

Chicago,  1919. 


CONTENTS 


Introduction 17 

Defuiitions 17 

The  Subdivision  of  Pharmacology 17 

Theories  and  Mode  of  Pharmacological  Action 18 

Results  of  Drug  Action 1  g 

General  Protoplasm  Actions  and  Ganeral  Poisons 20 

Chemical  Composition  and  Pharmacological  Action 21 

Conditions  Modifying  the  Effects  of  Drugs 22 

The  Fate  of  Drugs  in  the  Body 25 

The  Object  of  Pharmacology 25 

Methods  and  Equipment 28 

General  Technic 28 

Care  of  Tissues  and  Animals 29 

Anesthesia 29 

General  Principle 30 

Morphin  Ether 32 

Intratracheal  Insufflation 32 

Insufflation  Apparatus 34 

Anesthesia  by  Insufflation 34 

Pharj^ngeal  Insufflation 34 

Artificial  Respiration  and  Resuscitation  by  the  Meltzer  Method  35 

The  Schafer  Method  of  Artificial  Respiration  and  Resuscitation  37 

The  Marshall  Hall  Method 39 

The  Sylvester  Method 39 

The  Third  Resuscitation  Commission 39 

CHAPTER  I. 

Modes  of  Administering  Drugs. 

Frogs 44 

Mammals 44 

Operative  Technic 47 

Exposure  of  Nerves 47 

Stimulation  of  Nerves 47 

Placing  a  Cannula  in  the  Trachea 47 

Injecting  into  a  Vein 49 

Inserting  a  Cannula  into  the  Carotid  Artery 49 

Opening  th(;  Thoracic  Cavity 50 

Rticording  lilood-pressure  in  Mammals 51 

(Jleanirig  Out  the  Cannula 52 

Ii<;cording  R(;.spiration 52 

Graphic  Records ....  53 


vi  CONTENTS 

CHAPTER  II. 

Experimental  Pharmacology. 

Local  Action  of  Drugs 57 

Local  Anesthesia 57 

Demulcents 62 

Emollients 63 

Dusting  Powders 64 

Local  Irritants 65 

Skin  Irritants  and  Rubefacients 68 

Steps  in  the  Action  of  Irritants 68 

Caustics  or  Escharotics 69 

Symptoms  and  Treatment  of  Caustic  Poisoning 70 

CHAPTER  III. 

Pharmacology  of  the  Gastro-intestinal  Tract. 

Bitters 71 

Simple  Bitters 71 

Aromatic  Bitters 72 

Astringent  Bitters 72 

Compound  Bitters 72 

Local  Action 72 

Carminatives 74 

Volatile  Oils 74 

Emetics 77 

Purgatives  or  Cathartics 78 

Obstipants  or  Astringents •.      .      .      ...      .      .  81 

Acids 82 

Metallic  Salts 82 

Calcium  Hydroxide 82 

Alkaloids 83 

Atropin 83 

Inert  Powders 83 

Anthelmintics        .      .   - 84 

Secretions — Movements — ^Antisepsis 85 

Movements 85 

Absorption 85 

Excretion  of  Drugs  into  the  Intestine 86 

Intestinal  Movements 86 

Intestilial  Antisepsis 87 

CHAPTER  IV. 

Antiseptics  and  Disinfectants. 

General  Disinfectants  and  Deodorizers 88 

Disinfectants  of  Surgical  SuppUes 88 

Genito-urinary  Disinfectants 88 


CONTENTS 


Vll 


Intestinal  Antiseptics 89 

Antiseptic  Dusting  Powders 89 

Drjing  or  Absorbent  Powders 90 

Antiseptic  Action  of  Alcohol 90 


CHAPTER  V. 

Drugs  Characterized  by  their  Action  Chiefly  after  Absorption. 

Drugs  Acting  upon  the  Cerebrum 91 

The  Alcohol  Group 91 

Alcohol  as  a  Food 92 

Effect  of  Drugs  on  Motor  Areas 93 

Eflfect  of  Anesthesia  on  Motor  Areas 94 

Effects  of  Strychnin  on  Motor  Areas 94 

CHAPTER  VI. 

Pharmacology  of  the  Cranial  Ner\-es. 

The  First  Nerve:  N.  Olfactorius 96 

Chemistry  and  Physics  of  Odors 97 

The  Second  Nerve:  N.  Opticus 98 

Drugs  Acting  on  the  Optic  Nerve 98 

The  Third  Nerve :  N.  Oculomotorius 99 

The  Fourth  Nerve:  N.  Trochlearis 100 

The  Fifth  Nerve:  N.  Trigeminus 100 

The  Sixth  Nerve:  N.  Abducens 100 

The  Seventh  Nerve :  N.  Facialis 100 

The  Eighth  Nerve:  N.  Acousticus 101 

The  Ninth  Nerve:  N.  Glossopharyngeus 101 

The  Tenth  Nerve:  N.  Vagus 104 

The  Eleventh  Nerve:  N.  Accessorius 104 

The  Twelfth  Nerve :  N.  Hypoglossus 104 


CHAPTER  VII. 

Pharmacology  OF  the  Heart  and  Blood-pressure. 

Blood-pressure 

Methods  of  Lowering  Blood-pressure 

Methods  of  Increasing  Blood-pressure 
Digitaloid  Drugs  and  Digitalis  .... 

Action  on  the  Frog  or  Turtle  Heart    . 

Action  on  Turtle  Heart  Strips 

Effect  on  I  leart  Beat 

Action  of  Digitalis  on  the  Heart  and  Resj)iration  of  a  Dog 

Action  of  Digitalis  on  the  Heart  and  Resi)iration 

Myocardiagram  and  lilood-pressun;  under  Digitalis 


107 
107 
108 
109 
110 
110 
110 
110 
112 
112 


viii  .     CONTENTS 

Digitalis  as  a  Diuretic 112 

Standardization  of  Digitalis 112 

Hatcher's  Cat  Method      .• 114 

Gold  Fish  Method  of  Pittinger  and  Van  der  Kleed      ....  115 

Standardization  of  Suprarenal  Gland 115 

Aconitin 116 

Action  of  Aconitin  on  a  Frog 117 

Action  of  Aconitin  on  Blood-pressure       .      . 117 

Effects  of  Aconitin  on  a  Dog 117 

Squibb's  Test  for  Aconitin 118 

The  Bio-assay  of  Aconitin 118 

The  Nitrites 118 

Action  of  Nitrites  on  the  Circulation  and  Respiration 118 

Action  of  Nitroglycerin 119 

Action  of  Sodium  Nitrite  Injected  Intravenously 119 

Influence  of  Atropin  on  Nitrite  Action     . 119 

Effect  of  Amyl  Nitrite  on  Students 119 

Action  of  Nitrites  on  Frogs 119 

Influence  of  Nitrites  on  Bloodvessels 119 

The  Action  of  the  Alcohol  Chloral  Group  on  the  Pupil,  Heart  and  Reflexes  121 

Reflex  Time  as  Changed  by  Alcohol 121 

Crossed  Reflex  Time •  122 

Effect  of  Alcohol  on  Reaction  Time 123 

Ether  and  Chloroform  Anesthesia 124 

Action  of  Alcohol  on  a  Normal  Dog 126 

Ether  Anesthesia 126 

Effect  of  Alcohol  on  Frogs 127 

Effect  of  Alcohol  on  Reflex  Time 127 

Effect  of  Alcohol  on  the  Heart  of  a  Frog 128 

The  Effects  of  General  Anesthetics  on  the  Circulation,  Respiration  and 

Temperature 129 

The  Direct  and  Reflex  Effect  of  Ether  and  Chloroform  on  the  Heart  130 

Effect  of  Ether  and  Chloroform  on  Mammals 130 


CHAPTER  VIII. 

The  Closed  Method  of  Anesthesia. 

Nitrous  Oxide  Anesthesia  on  the  Dog 132 

Nitrous  Oxide  on  Frogs 132 

The  Specific  Action  of  Nitrous  Oxide 133 

Bromides 133 

Cannabis 134 

Effect  of  Cannabis  on  a  Dog 134 

Comparison  of  Action  of  Morphin  Bromides  and  Cannabis     .      .      .  135 

Assay  of  Cannabis 135 


CONTENTS  ix 


CHAPTER  IX. 

Action  of  Strychnin,  Picrotoxin  and  Curara  on  the  Central 
Nervous  System. 

Effect  of  Strychnin  on  Frogs 237 

Seat  of  Action  of  Strychnin 2^7 

Determination  of  the  Relation  of  Sensory  Stimuli  to  the  Production  of 

Convulsions 100 

Claude  Bernard's  Experiment ^30 

Action  of  Strychnin  on  Turtle  Heart  Strips I39 

Action  of  Strychnin  on  Mammals 23g 

Action  of  Strychnin  on  Heart  and  Respiration I39 

Synergism  of  Strychnin  and  Cocain 240 

Caffein -..r^ 

Action  of  Curara  on  the  Central  Nervous  System  of  Mamma's      ...  140 

Effect  of  Curara  on  Muscle  Contraction 242 

Action  of  Strychnin  on  Reaction  Time 241 

Action  of  Strychnin  on  the  Ear 241 

Action  of  Strychnin  on  the  Eye 241 

CHAPTER  X. 

Paralysis  of  Motor  Nerve  Endings. 

Curara ,.0 

Action  of  Curara  on  Mammals 243 

The  Central  Action  of  Curara 243 

Determination  of  Motor  Paralysis 244 

Action  of  Curara  on  Muscle-nerve  Preparation I44 

Curara  on  Non-anesthetized  Animals 245 

Stimulation  of  Motor  Nerve  Endings 245 

Symptoms  Following  the  Intravenous  Injection  of  Curara       ...  146 

Respiration  as  .\ffected  by  Curara  and  Physostigmin 146 

CHAPTER  XI. 

Pharmacology  of  Sensory  Nerve  Ends. 

Cocain ,  ,- 

Local  Anesthetic  Action  of  Cocain 247 

Cocain  Substitute 247 

General  Action  of  Cocain  on  Frog 247 

Result  of  Intravenous  Injection  of  Cocain  in  Mammal        ....  147 

Action  of  Cocain  on  Heart  Musch; 247 

l^fTect  of  Cfjcain  on  Muscle  Tissue; 248 

Effect  of  (Jocain  on  the  Circulation  and  Respiration  of  Mammals      .  148 

Spinal  Anesthesia 248 

Action  of  Cocain  on  Temiierature 248 

Local  Anesthesia  in  Man 248 


X  CONTENTS 

CHAPTER  XII. 

Autonomic  System  and  Autonomic  Drugs. 

Differences  between  Sympathetic  and  Parasympathetic  System     .      .      .  149 

Autonomic  Drugs 152 

Atropin  and  Pilocarpin  Group 152 

Action  of  Pilocarpin  Nitrate 152 

Action  of  Atropin  Sulphate 152 

Effect  of  Atropin  on  the  Eye 153 

Action  of  Atropin  on  the  Frog  and  Turtle  Heart 154 

Action  of  Pilocarpin  and  Atropin  on  Turtle  Heart  Strips   .      .      .      .  154 

Effect  of  Atropin  and  Pilocarpin  on  the  Volume  of  the  Respired  Air   .  155 

Action  of  Pilocarpin,  Physostigmin  and  Atropin  on  Uterine  Strips     .  155 

Action  of  Atropin  and  Physostigmin  on  the  Intestinal  Movement      .  155 

Action  of  Atropin  and  Pilocarpin  on  a  Pithed  Dog 155 

Antagonism  of  Atropin  to  Morphin 157 

Nicotin 157 

Selective  Action  of  Nicotin  on  Ganghon  Cell 157 

Action  of  Nicotin  on  Blood-pressure  and  Heart 158 

General  Effect  of  Nicotin  on  the  Frog 158 

Nicotin  in  Tobacco  Smoke 159 

Toxicity  of  Nicotin 159 

Effect  on  Respiration  when  Given  Intravenously 159 

Effect  on  Reflexes 159 

Influence  on  Epinephrin  Action 159 

CHAPTER  XIII. 

Pharmacology  of  the  Eye. 

Drugs  Acting  on  the  Lacrimal  Glands '     .  160 

Drugs  Stimulating  the  Retinal  Cells  or  Vision 160 

Drugs  Depressing  the  Retinal  Function 160 

The  Iris  and  the  CiUary  Muscle 161 

Drugs  Stimulating  the  Third  Nerve  (Parasympathetic  Endings)    .      .      .  161 

Drugs  Paralyzing  the  Third  Nerve  Endings 161 

Drugs  Stimulating  the  Sympathetic  Nerves  to  Radiating  Fibers    .      .      .  161 

Drugs  Paralyzing  the  Sympathetic  Nerve  Endings  in  the  Eye        .      .      .  161 

Drugs  Changing  the  Size  of  the  Pupil  by  a  Central  Action        .      .      .      .  161 

CHAPTER  XIV. 

Antagonism. 

Physiological  Antagonism 163 

Synergism 164 

Synergism  of  Morphin  and  Scopolamin 165 

Synergism  of  Morphin  and  Narcotin 165 

Synergism  of  Morphin  and  Papaverin 165 

Synergism  of  Morphin,  Scopolamin  and  Atropin 165 

Action  of  Scopolamin  and  Urethane 166 


CONTENTS  XI 

Epinephrin 1^6 

Action  of  Epinephrin  on  Blood-pressure  and  Respiration  ....  166 

Action  of  Epinephrin  on  Vasodilators 167 

Action  of  Epinephrin  on  Intestine 168 

Jackson's  Finger-cot  Method 169 

Action  of  Epinephrin  on  the  Uterus 169 

Barbour's  Method  of  Studying  the  Action  of  Drugs  on  the  Uterus    .  170 

Action  of  Epinephrin  on  the  Eye 170 

Action  of  Epinephrin  on  the  Secretions 170 

Glycosuria  Produced  by  the  Hypodermic  Injection  of  Epinephrin  171 

Action  of  Epinephrin  on  the  Tone  of  Bronchial  Muscle  171 

CHAPTER  XV. 

Antipyresis  and  Antipyretics. 

AntipjTetics 17^4 

Action  of  AntipjTetics 175 

Influence  of  Peptone  on  Antipyretics 175 

Effect  of  Chloral  Hydrate 175 

Hygienic  and  Drug  Treatment  of  Fever 176 

Heat  Centers 176 

Action  of  Ergot  and  Calcium  Lactate 176 

Effect  of  Hot  Water 176 

Destruction  of  Heat  Center 177 

CHAPTER  XVI. 

Pharmacology  of  the  Glands. 

Drugs  Affecting  the  Glands 178 

Salivarj'  Glands 179 

Gastric  Secretion 179 

Intestinal  Secretion 179 

Pancreatic  Secretion ISO 

CHAPTER  XVII. 

Pharmacology  of  the  Kidneys. 

Theories  of  Diuresis 181 

Important  Factors  Modifying  the  Secretion  of  Lhine 181 

Diuretics 182 

Antidiuretics 182 

Elimination  of  Drugs  by  the  Kidneys 183 

Caffein 183 

The  Diuretic  Action  of  Caffein 183 

Action  of  Caffein  on  the  Heart,  Respiration  and  Kidney    ....  184 

Action  of  Caff(!in  on  the  Frog 185 

Action  of  Caffein  on  the  Frog's  Heart 186 

Action  of  Caffein  on  the  Turtle  Heart 186 

.Action  of  (affein  on  Turtle  Heart  Strips 186 

Action  of  Caffein  on  the  Reflex  Time  of  Frogs 186 

Action  of  Caffein  on  Respiration 187 


xii  CONTENTS 

Saline  Diuretics 187 

Chemicals  as  Diuretics 188 

Diuretic  Action  of  Caffein  on  Normal  Animal 188 

Action  of  Diuretics  on  Human  Being 188 

Phenolsulphonephthalein 189 

Effect  of  Chemicals  on  Excretion  of  Phenolsulphonephthalein      .      .  189 

Effect  of  Various  Drugs  used  as  Diuretic 189 

Test  for  Phenolsulphonephthalein 189 

CHAPTER  XVIII. 

Pharmacology  of  Sweat  Glands. 

Function 191 

Distribution  of  the  Glands 191 

Innervation 191 

Endocrinal  Pharmacology 192 

CHAPTER  XIX. 

Pharmacology  of  the  Liver,  Mammary  Glands,  Uterus  and  Bladder. 

Pharmacology  of  the  Liver 193 

Main  Functions  of  the  Liver 193 

The  Glycogenic  Function  of  the  Liver 193 

Drugs  Influencing  the  Carbohydrate  Metabolism  of  the  Liver            .  194 

Pharmacology  of  the  Mammary  Glands 194 

Lactagogues '  195 

Elimination  of  Drugs  in  the  Milk 195 

Pharmacology  of  the  Uterus 195 

Epinephrin 195 

Atropin 196 

Physostigmin  and  Pilocarpin .  198 

Ergot 196 

Action  of  Ergot  on  the  Frog 196 

Action  of  Ergot  on  the  Arterioles 196 

Action  of  Ergot  on  the  Blood-pressure,  Respiralion,  Pupil  and 

Vagus  Tone 196 

Action  of  Ergot  on  Heart  Strips 197 

Action  of  Ergot  on  the  Uterus 197 

Standardization  of  Ergot 198 

Pharmacology  of  the  Bladder 200 

Antisepsis 200 

CHAPTER  XX. 

Pharmacology  of  the  Muscles. 

Voluntary  Muscles 201 

Involuntary  Muscles 202 

Classification  of  Drugs  Acting  on  Muscles 203 


CONTENTS  xui 

Pituitary  Extract,  Liquor  Hypophysis,  Pituitrin,  Infundiljulin,  etc.      .  204 

Action  of  Liquor  Hypophysis  on  the  Frog 204 

Action  of  Liquor  Hypophysis  on  the  Circulation 204 

Action  of  Liquor  Hypojjhysis  on  the  Heart 204 

Action  of  Liquor  Hypophysis  on  the  Heart,  Respiration,  Pupils    and 

Kidneys 205 

Action  of  Liquor  Hypophysis  on  the  Uterus 206 

Standardization  of  Pituitarj^  Extracts 207 

Nitrites 208 

Veratrin 208 

Quinin 209 

Action  of  Quinin  on  Yeast  Fermentation 210 

Action  of  Quinin  on  White  Corpuscles 210 

Action  of  Quinin  on  the  Frog  or  Turtle  Heart 210 

Action  of  Quinin  on  the  Heart  and  Respiration  of  a  Mammal       .      .  210 

Quinin  Urea  Hydrochloride 210 

Calcimn,  Barium  and  Magnesium  Salts 211 

Calcium  and  Magnesium  Antagonism 211 


CHAPTER  XXI. 

Pharmacology  of  the  Lymphatics. 

Effect  of  Peptone  on  Rate  of  Lymph  Flow 214 

Effect  of  K.  I.  sugar,  etc.,  on  Rate  of  Lymph  Flow 214 

Effect  of  Pilocarpin  and  Atropin  on  Rate  of  Lymph  Flow 214 


CHAPTER  XXII . 

General  Protoplasm  Poisons  and  Miscellaneous. 

Hydrocyanic  Acid ^ 215 

Action  of  Cyanides  on  Respiration,  Blood-pressure,  and  Blood  and 

Oxygen  Consumption 215 

Acids,  Alkalies  and  Corrosives 216 

Corrosive  Action  of  Acids  and  Alkalies 216 

Sulphides 217 

Action  of  Sulphides  on  Yeast  Fermentation 217 

Oxalates  and  Fluorides 218 

Iodides 218 

Excretion  of  Iodides 218 

Heavy  Metals 219 

UiC'A  Action 219 

General  Action          219 

Colloidal  Heavy  Metals 220 

Potassium  Salts 220 

Al)sori)tion  and  JOxcretion 220 

Action  of  Pota-:sium  Salts  on  the  Heart  and  Vessels      ...  220 

Action  of  Pota.Hsiuni  on  Reflex  Time         220 


XIV  CONTENTS 

Ammonium 221 

Effect  of  Intravenous  Injection  of  Ammonium  .      .      .      .      .      .      .  221 

Inhalation  of  Ammonia 221 

Experimental  Glycosuria 222 

Bernard's  Method  of  Puncturing  the  Floor  of  the  Fourth  Ventricle     .      .  222 

Ferments,  EnzjTnes  and  Digestants 225 

CHAPTER  XXIII. 

Pharmacology  of  the  Blood. 

Functions  of  the  Blood 227 

Volume  of  the  Blood 228 

Viscosity 228 

Clotting  of  the  Blood 230 

Means  of  Hastening  or  Retarding  Clotting 231 

Agents  Hastening  Clotting 232 

The  AlkaUnity  of  the  Blood  and  Acidosis 233 

Hydrogen  Ion  Concentration -  .  233 

Potential  Alkalinity 234 

Acidosis ....  235 

Specific  Gravity  of  the  Blood 235 

Laking  or  Hemolysis 235 

Nature,  Amount,  and  Changes  in  the  Hemoglobin 236 

Coagulation 237 

Effect  of  Adrenalin  and  Peptone  on  Clotting  Time 237 

Viscosity 237 

AlkaUnity  and  Acidity  Changes  in  the  Blood 238 

Hemolysis  or  Laldng 238 

Osmotic  Resistance  of  the  Corpuscles 238 

Fragihty  of  the  Corpuscles 238 

Crenation 238- 

Changes  in  the  Oxygen-carrying  Power  of  the  Blood,  Toxicology  .      .      .  238 

Carbon  Monoxide  Hemoglobin 238 

Methemaglobin .238 

Cyanhemoglobin 239 

Hematoporphyrin 239 

Permeability  of  the  Red  Corpuscles 240 

The  Presence  of  Drugs  in  the  Blood 240 

Carbon  Dioxide 242 

Lewis-Benedict  Methods  of  Determining  Blood-sugar 242 

Phloridzin 242 

Saponin 243 

List  of  Stock  Solutions 244 


EXPERIMENTAL  PHARMACOLOGY. 


INTKODUCTION. 

Definitions. — Pharmacology  is  the  term  used  to  include  all  knowl- 
edge pertaining  to  drugs  and  their  actions.  The  term  drug  comes 
from  the  Anglo-Saxon  word  drugan  =  to  dry.  It  w^as  first  used 
because  dried  plants  in  early  times  made  up  the  whole  materia 
medica.  The  term  has  grown  with  the  extension  of  the  materials 
used  in  medicine,  and  at  present  includes  everything  used  as 
medicine. 

Experuiiental  pharmacology  is  a  biological  science,  and  as  such 
is  related  to  general  biology,  especially  the  subjects  of: 

Anatomy. 

Physiology. 

Pathology. 

Chemistry  and  Biochemistry 
The  relation  to  biology  is  evident,  since  pharmacology  is  a  study 
of  the  reactions  of  living  material  to  changes  in  environment.  These 
changes  in  environment  are  usually  produced  by  drugs.  It  is 
related  to  anatomy,  since  this  science  is  necessary  as  a  foundation 
of  the  study  of  tissues.  If  we  do  not  know  the  anatomy  we  cannot 
interpret  physiological  reactions.  Physiology  is  the  study  of  the 
functions  of  tissue  and  organisms,  while  pharmacology  studies  the 
same  functions  as  modified  by  drugs.  It  is  related  to  pathology, 
since  the.  introduction  of  the  drugs  in  itself  is  a  pathological  condi- 
tion and  many  drugs  readily  create  distinctly  pathological  states. 
P'or  example,  phosphorus  may  cause  fatty  degeneration  of  the  liver, 
uranium  salts  may  cause  nephritis,  etc.  The  relation  to  chemistry 
and  to  biochemistry  is  obvious.  Drugs  are  chemicals,  and  the  reac- 
tions of  drugs  with  the  organism  is  definitely  a  branch  of  organic  or 
biologic  chemistry.  From  this  viewpoint  pharmacology  is  a  branch 
of  ii])])Vu'(\  organic  chemistry. 

The  Subdivisions  of  Pharmacology  are: 

Materia  medica. 

Pharmacy. 
2 


18  INTRODUCTION 

Pharmacognosy. 

Pharmacodynamics . 

Therapeutics,  including  prescription  writing  and  posology  or 

dosage. 
Toxicology. 

These  subdivisions  are  not  sharply  defined,  and  are  for  conveni- 
ence only. 

Materia  Medica. — ^Materia  medica  treats  of  the  source,  consti- 
tuents, physical  and  chemical  characteristics  and  doses  of  drugs. 

Pharmacy. — A  study  of  the  properties,  preparation,  compounding 
and  dispensing  of  medicines. 

Pharmacognosy. — Pharmacognosy,  gross  and  microscopic,  may  be 
considered  as  a  part  of  materia  medica,  and  deals  especially  with 
the  recognition  of  drugs  and  the  study  of  crude  materials.  In  the 
identification,  the  origin,  the  physical  properties,  chemical  reactions, 
taste,  odor,  microscopic  appearance,  etc.,  may  be  considered. 

Pharmacodynamics  or  Experimental  Pharmacology. — ^The  study  of 
the  action  of  drugs  on  the  living  organism  includes  clinical  observa- 
tions and  experience  as  well  as  experimental  work.  Toxicology  may 
be  considered  as  a  branch  of  pharmacodynamics.  In  the  widest 
sense,  pharmacodynamics  is  a  study  of  reactions  of  living  matter 
due  to  changes  in  environment. 

Therapeutics. — The  art  and  practice  of  treating  abnormal  states 
by  any  means  that  relieves  pain,  restores  health  or  prolongs  life. 
Any  change  in  environment  of  an  animal  will  have  this  effect,  and 
comes  under  the  term  pharmacology  in  its  broadest  meaning. 

Toxicology. — ^Toxicology  deals  with  the  symptoms,  diagnosis, 
treatment  and  detection  of  poisons. 

A  poison  may  be  defined  arbitrarily  as  any  substance  which,  when 
taken  by  mouth  in  doses  of  less  than  50  gm.  will  injure  health  or 
cause  death. 

The  distinction  between  foods,  drugs  and  poisons  is  hard  to  make. 
A  drug  is  anything  that  is  used  as  a  medicinal  agent.  Poison  has 
been  defined,  but  we  should  remember  that  there  is  no  definition 
entirely  satisfactory  or  generally  accepted.  A  food  is  something 
that  supplies  energy  to  the  body,  does  not  injure  the  body  when 
taken  by  mouth  and  will  build  up  the  tissue  and  repair  waste. 

Theories  and  Mode  of  Pharmacological  Action.- — ^The  action  of  drugs 
may  be  physical  or  chemical. 

Physical  Actions. — Physical  actions  are  those  in  which  there  is 
no  chemical  reaction  between  the  drug  and  the  tissues.  The  most 
important  physical  actions  are: 


INTRODUCTION  19 

1.  The  protective  effect  of  oils,  powders,  gums,  mucilage,  collo- 
dions, and  fixed  dressings. 

2.  The  osmotic  effects  (or  salt  action)  of  isotonic,  hypotonic  or 
h^•pertonic  solutions. 

3.  The  adsorptive  or  absorptive  action  of  carbon,  dyes,  etc., 
infusorial  earths  and  colloids  generally. 

Chemical  Actions. — Some  drugs  exert  a  chemical  reaction  within 
the  body.    The  nature  of  the  action  may  be : 

1.  Combination. — (a)  As  the  neutralization  of  an  acid  with  a 
base,  as  when  the  hydrochloric  acid  of  the  stomach  is  neutralized 
by  sodium  bicarbonate;  and  the  addition  of  HCl  with  NH3. 

(6)  Such  unknown  reactions  as  selective  affinity  are  probably 
chemical. 

2.  Solution. — The  Meyton-Overton  theory,  which  explains  anes- 
thesia as  a  solution  of  nervous  material  by  ether,  etc.,  is  a  chemical 
reaction.  It  should  be  remembered,  however,  that  chemists  hold 
different  opinions  regarding  the  nature  of  even  the  solution  of  salt 
in  water,  consequently  the  actual  reaction  in  solutions  may  mean 
something  different  even  to  experts. 

Results  of  Drug  Action. — This  is  only  a  modification  of  normal 
functions  or  of  the  fundamental  properties  of  living  matter.  The 
fundamental  properties  of  life  or  living  matter  are: 

1.  Metabolism — anabolism  and  katabolism — which  may  include 
all  digestive  processes. 

2.  Excitability  manifested  by  contractility,  conduction,  motility, 
.secretion,  etc. 

3.  Reproduction. 

Drugs  only  modify  these  properties — they  caimot  create  new 
functions. 

Drugs  can  act  then  only  by  stimulation,  depression  or  irritation 
of  the  normal  processes.  This  shows  clearly  the  relation  of  phar- 
macology to  physiology. 

By  stimulation  we  mean  an  increase  in  the  function  of  an  organ 
or  tissue. 

By  flepression  we  mean  a  decrease  in  function. 

In  irritation  the  change  is  more  anatomical  than  functional,  and 
some  of  the  signs  of  inflammation  are  present.  These  are  redness, 
local  increase  in  temperature,  swelling  and  pain.  There  may  be 
some  changes  in  function  which  are  of  a  secondary  nature. 

Drugs  may  also  cause  fatigue  and  paralysis,  which  are  also 
modifications  of  function.  The  causes  of  fatigue  may  be  due 
to: 


20  INTRODUCTION 

1.  The  exhaustion  of  energy-yielding  material. 

2.  The  accumulation  of  waste  products. 

Experiments  have  shown  that  the  order  of  the  occurrence  or  ease 
of  fatigue  in  the  various  tissues  are: 

1.  Nerve  center. 

2.  Nerve  endings. 

3.  Muscle. 

4.  Nerve  fibers. 

Recovery  from  fatigue  takes  place  with  rest  alone  {cf.  Paralysis) . 

Paralysis. — This  may  also  be  caused  by  a  drug.    It  is  due  to  a 

combination  of  the  drug  with  the  cell  substance  and  recovery  takes 

place  only  when  the  drug  is  removed  (cf.  Fatigue  and  Curare  Action). 

The  curare  effect  or  action  is  a  paralysis. 

Paralysis  may  also  be  caused  by  anatomical  changes  or  lesions. 
It  is  obvious  that  in  some  of  these  recovery  cannot  be  expected. 
There  are  also  many  in  which  fatigue  and  paralysis  cannot  be 
separated  or  distinguished,  so  there  are  conditions  in  which  there 
is  ground  for  a  legitimate  difference  of  opinion.  One  must 
remember  that  when  the  problem  of  life  itself  is  up  for  explana- 
tion, dogmatic  assertions  cannot  always  be  made. 

Elective  Affinity  or  Selective  Action. — ^When  a  drug  is  introduced 
into  the  body  and  it  acts  more  on  one  tissue  than  another  we  say 
its  action  is  selective.  It  would  perhaps  be  better  to  say  the  tissue 
action  is  selective,  e.  g.,  curare  acts  on  the  nerve-endings  to  striated 
muscle  almost  to  the  exclusion  of  other  actions.  Epinephrin  acts 
on  the  endings  of  the  sjanpathetic  nerves.  Many  other  drugs  show 
this  tendency  to  pick  out  a  particular  tissue  and  exert  its  action  on 
it  to  the  exclusion  of  others.    Such  actions  are  said  to  be  selective. 

General  Protoplasm  Actions  and  General  Poisons. — If  a  drug  acts 
on  tissues  generally  without  exhibiting  an  action  on  one  more  than 
another  we  say  it  has  a  general  protoplasmic  action,  and  if  toxic 
it  is  a  general  protoplasmic  poison. 

Local,  Remote  and  General  Actions. — In  many  cases  whether  a 
drug  exerts  a  local  or  remote  action  depends  on  the  concentration 
and  the  mode  of  application. 

Local  Action. — ^Most  drugs  that  are  not  absorbed  have  local 
action  only,  e.  g.,  demulcents  and  emollients;  Bi  and  Ag  salts; 
sprays  in  nose  or  throat;  dusting  powders  and  protectives  act  only 
where  they  are  applied  and  the  action  is  mainly  of  a  physical 
nature. 

By  remote  or  indirect  action  we  mean  an  action  elicited  in  organs 
away  from  the  site  of  application.    Irritation  of  the  skin,  blisters 


INTRODUCTION  21 

or  cold  applications  in  any  region  may  influence  the  rate  of  the 
heart  indirectly  through  the  nervous  system.  Cerebral  depressants 
in  the  same  way,  by  lessening  movement,  lessen  oxidation  in  the 
muscles.  Atropin  injected  in  the  arm  has  no  action  locally  but 
causes  an  increased  heart-rate,  because  when  carried  in  the  circula- 
tion it  paralyzes  the  vagus  endings. 

By  general  action  we  mean  those  actions  that  cannot  be  fixed  on 
any  one  tissue,  as  the  action  of  tonics,  sedatives  and  the  like. 

Since  all  drugs  may  also  be  poisons,  Loew's  theory  of  the  action 
and  his  classification  of  poisons  may  be  given. 

He  classifies  poisons  as: 

(a)  General. — The  general  poisons  are  subdivided  into: 

1.  Oxidizing: 
Ozone. 
Peroxides. 
Permanganates. 
Chromates. 
Hypochlorites,  etc. 

2.  Catalytic:  These  do  not  undergo  any  apparent  change  them- 
selves, but  act  on  protoplasm.  The  volatile  narcotics  and  enzjmes 
are  examples. 

3.  Salt-forming:  Due  to  the  amphoteric  character  of  the  proto- 
plasm, some  drugs,  like  acids,  alkalies,  tannins,  etc.,  combine  to 
form  salts. 

4.  Substituting:  These  include  all  bodies  which  react  with  alde- 
hydes and  amins,  forming  substitution  products.    Such  drugs  are: 

Hydrazine. 

Phenol  hydrazine. 

Anilin. 

Ammonia. 

Phenol. 

Hj'drocyanic  acid. 

Hydrogen  sulphide  and  sulphites. 

(b)  Special  or  Selective  Poisons. — These  include  toxins,  anti- 
toxins and  the  selective  acting  drugs,  such  as: 

Atropin. 
Strychnin. 
Curara. 
Eserin. 
Nicotin,  etc. 
Chemical  Composition  and  Pharmacological  Action. — All  pharma- 
cological actions  are  either  chemical  or  i)hysical.     Hut  all  pharma- 


22  INTRODUCTION 

cological  action  is  exerted  on  and  causes  changes  in  the  physical  and 
chemical  bases  of  life. 

The  physical  bases  of  life  are  a  viscid  medium,  a  colloidal  solution 
of  proteids,  salts,  and  water. 

The  Chemical  Essentials  of  Life  Are: 

1.  An  energy-yielding  substance. 

2.  Conditions  suitable  for  their  reaction  and  liberation  of  energy. 

3.  Proper  temperature. 

4.  Alkalin  reaction. 

5.  Ferments. 

6.  The  presence  of  certain  apparently  essential  chemical  elements, 
e.  ST.,  C,K,S,  N,  CI,  Fe,  O,  P,  Mg. 

With  constant  conditions  we  should  expect  a  related  action  in  a 
homologous  chemical  series,  and  in  the  paraffin  series  of  alcohols, 
Baer  gives  the  following  ratio  of  toxicity  for  alcohols: 
Methyl,  0.8. 
Ethyl,  1.0. 
Propyl,  2.0; 
Butyl,  3.0. 
Vinyl,  4.0. 

As  a  matter  of  fact,  however,  such  a  relation  is  very  rare,  and 
while  we  might  always  expect  a  relation  between  the  action  of  drugs 
and  their  chemical  composition,  there  is  more  relation  between  their 
physical  properties  and  the  action.  This  is  largely  because  we  know 
only  the  elements  of  the  chemistry  of  the  body.  At  the  same  time 
we  must  remember  that  no  one  can  even  predict  with  certainty  the 
action  of  the  pure  chemicals  whose  chemistry  is  well  known.  While 
we  would  expect  the  sulphides  and  the  phosphates  of  the  heavy 
metals  to  be  alike  in  color  and  solubilities,  there  are  many  exceptions 
which  can  be  determined  by  experiment  only.  With  the  animal 
organism  the  exceptions  are  more  numerous  than  the  conformities. 

There  is  no  law,  therefore,  known  to  exist  between  the  chemistry 
of  a  drug  and  its  reaction.  Future  work,  however,  will,  we  believe, 
ultimately  establish  such  a  law.  Chemical  pharmacology  should 
therefore  be  studied  as  much  as  pharmacodynamics  and  offers  more 
avenues  of  advance. 

Conditions  Modifying  the  Effects  of  Drugs. — These  are : 

1.  Hahit. — This  usually  lessens  the  effect  to  some  extent. 

2.  Size  and  Weight. — Smaller  persons  require  less  than  larger. 

3.  Age. — ^Young  persons  or  animals  require  less  than  old. 

The  rule  of  dosage  is  as  follows:  The  adult  dose  divided  by  the 
age  plus  twelve  gives  the  dose  for  a  child,  e.  g.,  the  dose  for  a  child  of 


INTRODUCTION  23 

foiir  years  of  a  drug  whose  dose  is  1  gram  for  an  adult  would  be 
|-  +  12  =  J  gram.    This  is  Young's  rule. 

There  are  other  rules,  but  this  one  is  most  used. 

Opiimi  and  morphin  are  exceptions  and  the  dose  given  should 
be  smaller  than  the  calculated  dose. 

4.  Women,  chiefly  because  oj  size,  should  get  only  four-fifths  of  the 
dose  for  men  (idiosyncrasy  is  more  often  found  in  females) . 

5.  Temporary  conditions,  such  as  meals,  irritations  and  inflamma- 
tory conditions,  neurasthenia,  diarrhea  and  vomiting,  pregnancy 
and  lactation  (drugs  excreted  in  milk)  must  be  considered  in  dosage. 

6.  Time  of  administration:  Stomachics  are  best  given  about 
thirty  minutes  before  meals;  cathartics,  when  convenient  for  patient 
and  narcotics,  at  night. 

7.  Idiosyncrasy:  Some  persons  have  a  peculiar  susceptibility  to 
drugs  and  react  to  a  small  dose  in  a  manner  that  would  indicate  that 
many  times  the  amount  had  been  given.  Congenital  tolerance  may 
be  considered  as  an  idiosyncrasy,  but  in  this  case,  the  organism  is 
exceedingly  resistant  to  the  drug. 

8.  Tolerance  differs  from  immunity  in  that  there  are  no  anti- 
bodies formed  in  tolerance.  While  there  are  in  immunity  it  has  not 
been  shown  that  any  chemical  substances  except  proteins  produce 
antibodies.^ 

9.  Some  drugs  exert  a  cumulative  effect  due  to  irregularity  of 
absorption — digitalis(?) — or  slower  excretion  than  absorption, 
which  may  occur  with  many  drugs  when  kidney  function  is 
depressed. 

10.  Synergists  or  Syngerism:  Mixtures  of  purgatives;  mixtures  of 
anesthetics;  alcohol  and  acetonitril;  narcotin  and  morphin,  etc.,  act 
in  some  cases  to  accentuate  the  action  of  each  other,  and  we  get 
more  than  the  additive  action  of  the  two.  Such  action  is  called 
synergistic.    Note  that  it  is  more  than  an  additive  action. 

11.  Antagonism. — Chemical  or  Therapeutic  Incomyatihility . — 
Some  drugs  antagonize  the  action  of  others,  e.  g.,  strychnin  and 
chloroform,  alcohol  and  caffein,  pilocarpin  and  atropin.  Drugs  that 
antagonize  each  other  and  should  not  be  administered  at  the  same 
time. 

12.  Pathological  Conditions. — Modify  drug  action.  Anti])yretics 
reduce  the  temi)erature  in  fever  but  not  in  the  normal  animal. 
Bromides  lessen  nervous  irritability  in  epilepsy  more  than  in  normal 
states.  Morphin  in  pain  reduces  sensitivity,  but  has  less  effect  in 
health. 

'  For  a  review  of  the  literature  ret'ardirifz  morpliiti  as  u  prodiifcr  of  anlilxxlics,  see 
Du  Moz,  Jour.  Am.  Med.  Amsm.,  1919,  Ixxii,  1009. 


24  INTRODUCTION 

The  Method  of  Administration  Modifies  the  Action  of  a  Drug.^ — While 
we  cannot  in  many  cases  correlate  chemical  composition  and  phar- 
macological action,  we  know  that  the  concentration  or  mass  action 
of  chemistry  holds  true  in  the  action  of  drugs  in  the  body.  It  is  for 
this  reason  that  drugs  react  differently,  depending  on  the  method 
of  application, 

1.  Introduction  of  Drugs  hy  Mouth. — This  is  the  usual  method, 
and  unless  there  is  good  reason  to  the  contrary,  should  be  the 
method  used.  But  absorption  is  slower  by  this  method  than  by 
most  others,  consequently  the  drug  reaches  the  tissues  slowly  and 
may  be  oxidized  or  excreted  almost  as  quickly  as  absorbed.  This 
explains  why  drugs  act  in  a  relatively  mild  way  when  given  by 
mouth. 

2.  Introduction  by  Rectum. — Drugs  are  sometimes  given  by  this 
method  to  avoid  action  on  the  mouth  and  stomach  and  reflexes 
that  might  be  exerted  on  the  heart.  They  are  absorbed  more  rapidly 
than  when  given  by  mouth,  and  the  dose  should  be  smaller.  Usually 
it  is  one-half,  though  some  give  twice  the  dose,  given  by  mouth. 

3.  Hypodermic  Injections. — Drugs  given  in  this  way  are  very 
quickly  absorbed.  They  are  absorbed  still  more  rapidly  if  given  by 
intramuscular  injection. 

4.  Intramuscular  Injection. — Deep  injection  into  the  skeletal 
muscles,  preferably  the  gluteus  or  deltoid.  There  is  less  pain  and 
tenderness  caused  by  drugs  that  are  irritating  when  given  deep  into 
the  muscles  than  when  the  injection  is  more  superficial.  Absorption 
by  this  method  is  also  quicker  than  by  any  other  method  of  adminis- 
tration except  the  intravenous  method. 

5.  Intravenous  Injection. — ^When  drugs  are  injected  into  the  vein 
they  are  applied  directly  to  the  point  of  action  as  quickly  as  the 
circulation  can  carry  them.  This  was  originally  a  laboratory  method, 
but  is  much  used  clinically  at  present.  It  is  too  frequently  used  in 
clinical  medicine  and  should  not  be  used  except  when  it  is  decidedly 
preferable  to  other  methods.  It  is  surprising  how  easily  and  how 
apparently  non-irritating  such  caustic  drugs  as  sodium  carbonate 
may  be  injected  intravenously,  while  if  injected  subcutaneously 
or  intramuscularly  they  may  produce  sloughing.  Strongly  alkalin 
or  acid-reacting  solutions  should  never  be  given  subcutaneously. 

6.  Transfusion  of  Blood  from  the  Artery  of  one  person  to  the  vein 
of  another,  or  from  one  animal  to  another,  is  much  used  in  cases 
of  hemorrhage,  anemias,  etc.,  and  in  investigative  work. 

7.  Inhalation. — Inhalation  is  the  usual  method  of  giving  general 
anesthetics.    It  depends  on  the  fact  that  some  drugs  may  be  absorbed 


INTRODUCTION  25 

from  the  lungs.  Insufflation  or  inhalation  is  also  used  in  nasal 
douches,  etc.  The  advantages  of  inhalation  is  that  the  amount  of  the 
drug  is  readily  controlled  and  removed.  By  the  other  methods  if 
excess  has  been  given  it  cannot  be  removed  readily. 

8.  Intraspinal  Administration. — By  this  method  drugs  are  intro- 
duced into  the  spinal  canal.  The  needle  is  introduced  between  the 
vertebrae,  and  the  flow  of  fluid  from  the  needle  indicates  when  the 
needle  is  in  place.  In  experimental  work  the  fourth  ventricle  may 
also  be  entered.  Care  must  be  used  in  clinical  work  to  keep  the 
patient  in  a  rigidly  fixed  position.  As  the  reflex  movement  that 
anyone  is  likely  to  make  when  the  needle  enters  the  spinal  canal 
may  break  the  needle  in  the  canal  and  this  is  a  serious  accident.  It 
should  never  be  tried  on  the  human  being  without  special  instruction. 

9.  The  local  application  of  drugs  needs  no  comment. 

10.  Sublingual. — Some  drugs  like  nitroglycerin  are  in  some  cases 
best  given  by  holding  the  tablet  under  the  tongue.  It  dissolves 
readily  and  is  absorbed  very  quickly. 

11.  Insufflation. — Powders  are  frequently  insufflated  or  blown  on 
to  a  surface.  Boric  acid,  e.  g.,  is  administered  to  the  ear  drum  or 
other  relatively  inaccessible  parts  in  this  way. 

The  Fate  of  Drugs  in  the  Body. — Drugs  in  the  body  may  be  oxidized 
and  then  excreted  by  any  of  the  excretory  organs.  Catalytic  drugs 
like  ether  are  excreted  unchanged  either  by  the  lungs,  skin,  kidneys 
or  intestinal  tract.  Most  drugs  are  oxidized  to  some  degree.  Others, 
like  the  oxalates,  are  combined  with  calcium,  and  still  others,  like 
the  saline  cathartics,  may  be  excreted  in  great  part  unchanged.  In 
studying  what  the  action  of  the  drug  is  on  the  body,  the  fate  of  the 
drug  or  what  the  action  of  the  tissues  is  on  it  should  also  be  studied. 

The  Object  of  Pharmacology. — Pharmacology  may  be  studied  as  a 
science  without  reference  to  its  application.  The  great  interest, 
however,  lies  in  its  relation  to  the  treatment  of  disease  and  to  the 
foundations  which  it  may  lay  for  therapeutics.  As  long  as  we  are 
ignorant  of  how  a  drug  acts  its  use  is  empirical,  unscientific  and 
unsatisfactory.  The  objects  of  experimental  pharmacology  is  to 
make  every  endeavor  to  explain  the  mysteries  of  therapeutics,  and 
it  makes  little  difference  where  this  is  done.  In  all  cases,  however 
the  bedside  is  the  court  of  final  ai)peal.  But  clinical  experience  must 
be  actual  not  imaginative.  One  of  the  oldest  practitioners  in 
America  recently  said  that  some  physicians  make  the  same  mistake 
one  hundred  times  and  call  it  experience.  Experience  must  be 
expressed  in  definite  measured  physical,  chemical,  physiological  or 
psychological  terms,  otherwise  experience  is  of  the  same  value  as 


26  INTRODUCTION 

gossip  in  a  court  of  law.  Clinical  and  laboratory  data  can  be 
expressed  in  these  terms  and  are  of  no  value  if  not  so  expressed. 
Mere  belief  that  digitalis  raises  the  blood-pressure  or  slows  the  heart 
is  of  no  value  unless  it  can  be  proved,  and  actual  measurements  are 
made.  All  established  therapeutic  agencies  have  at  one  time  passed 
through  the  experimental  stage,  some  are  still  in  this  stage. 

The  following  work  is  framed  with  the  idea  that  it  may  aid  the 
methods  of  recording  and  the  inclination  to  measure  changes  in 
the  function  of  organs  produced  by  drugs. 

METHODS  AND  EQUIPMENT. 

The  success  of  a  laboratory  course  in  pharmacology  depends  to  a 
large  degree  on  the  facilities  provided.  For  this  reason  the  apparatus 
needed  should  be  easily  available  and  in  working  order.  Adequate 
space  should  be  provided  for  keeping  the  apparatus.  Some  articles 
needed  but  rarely  may  be  provided  only  when  required.  The  greater 
part,  however,  should  be  in  the  custody  of  the  student  All  appa- 
ratus that  is  returnable  in  working  condition  should,  as  far  as  pos- 
sible, be  furnished  to  the  student. 

The  lockers  for  each  group  of  students  should  contain  the 
following : 

2  semicircular  stands. 

5  clamps. 

2  induction  coils. 

2  electrodes. 

1  ether  mask. 

1  perfusion  bottle. 

1  Woulff  bottle. 

2  funnels. 

2  flasks— 250  c.c. 

2  tumblers. 

2  beakers. 

2  electric  keys. 

2  evaporating  dishes. 

2  frog  boards. 

1  mesentery  board. 

1  dissecting  needle. 

2  25  c.c.  graduates. 
1  aneurysm  needle. 
4  Mohr  clamps. 

1  cork  plate  with  pins. 

1  knitting  needle. 

2  pithing  wires. 
1  brass  T-tube. 

1  box  with  2  glass  Y's,  1  glass  T's  and  6  vessel  cannulse. 

2  camel's-hair  brushes. 
2  tracheal  cannulse. 

1  screw  clamp. 

1  large  screw  clamp. 

1  tracheal  tube. 

2  heart  levers. 


METHODS  AND  EQUIPMENT  27 

4  muscle  levers — 2  straight,  2  elbow. 

4  watch  glasses. 

2  bundles  of  ligatures. 

1  suture  needle. 

2  feathers. 

2  10  c.c.  pipettes  graduated  in  jVths. 
2  10  c.c.  pipettes  graduated  in  ^V^hs. 
1  clinical  thermometer. 
1  thermometer,  1°  C.  to  100°  C. 
1  blood-pressure  pipette. 

1  electric  signal  magnet. 

2  glass  rods. 

1  sjTinge,  10  c.c.  graduated  jo  cc. 
1  sjTinge,  1  c.c.  graduated  juij  c.c. 

4  needles  in  a  bottle. 

1  femur  clamp. 

2  kj'mographs. 
2  extra  drums. 

1  100  c.c.  cylindric  graduate. 

1  stomach  tube  and  bulb. 

2  gags,  large  and  small. 
2  G-clamps. 

1  mercury  manometer. 
1  burette,  stand,  clamp  and  tube. 
10  test-tubes  with  rack  and  brush. 
1  sauce  pan. 

1  artificial-respiration  bellows. 
1  set  of  ropes. 

sponge,  sandpaper,  wax,  slides,  parchment,  towels,  electric  connection  wires. 
1  pair  of  dividers. 

1  millimeter  rule  10  cm.  long. 

2  celluloid  triangles. 

In  addition  to  the  equipment  provided  by  the  laboratory,  each 
student  should  come  provided  with  the  following: 

For  operating: 

1  scalpel. 

2  scissors. 

2  hemostatic  forceps. 
2  bulldog  clamps. 

1  operating  gown. 

2  towels. 

2  curved  needles,  large  and  small. 

2  pairs  of  thumb  forceps — one  large  and  one  small  curved. 
For  notes: 

6  sheets  of  cross-section  paper. 
50  sheets  of  thin  note  paper. 

5  sheets  of  carbon  paper  8]  x  12  inches. 

Laboratory  exercises  should  be  assigned  in  advance.  Each 
student  shouUl  study  them  thoroughly  before  coming  to  class.  He 
should  know  what  to  expect  and  if  the  unexpected  happens,  he 
should  know  the  reason,  because  results  are  always  obtained  accord- 
ing to  the  conditions  under  which  the  experiment  is  ])erf()rmed. 
Full  recfjrds  of  each  exi)eriment  should  be  kept.  It  is  impo.ssible 
for  each  man  to  keep  his  own  record;  but  those  of  the  group  who 
are  busy  with  the  f)perati()n  may  be  provided  witli  a  carl)on  copy 
prepared  by  the  secretary  of  the  group.     Before  commencing  an 


28  INTRODUCTION 

experiment,  each  student  should  have  a  definite  part  to  play  and 
should  attend  to  this  alone.    Cooperation  is  essential  to  good  work. 

GENERAL  TECHNIC. 

Fluids  which  come  in  contact  with  the  cells  of  the  body  or  with 
living  tissues  should  approximate  as  closely  as  possible  the  fluids 
which  normally  bathe  these  cells  or  tissues.  Lymph  and  blood  are 
the  true  physiological  solutions.  It  is  obviously  impossible  to 
approximate  these  without  great  care  and  time-consuming  pro- 
cedures. Several  of  the  so-called  salines  are  adequate  for  most 
operations  and  can  be  made  with  slight  effort.  They  are  isotonic, 
i.  e.,  they  have  approximately  the  same  osmotic  tension  as  blood. 
Those  most  in  use  are: 

1.  Physiological  Saline. — This  is  merely  a  solution  of  sodium 
chloride  in  water.  It  should  be  approximately  isotonic  with  the 
cell  protoplasm.  For  mammals  a  0.9  per  cent,  solution,  and  for 
amphibia  a  0.65  per  cent,  solution  will  be  found  satisfactory. 
Although  sodium  chloride  is  quantitatively  the  most  important 
saline  constituent  of  protoplasm,  the  presence  of  several  other 
difPusable  salts  is  necessary  to  normal  functioning.  When  cells  are 
exposed  to  simple  normal  saline  these  substances  soon  diffuse  out. 

2.  Ringer's  Solution. — This  more  nearly  approximates  the  normal 
tissue  fluid  and  therefore  prevents  most  of  the  diffusion. 

For  mammals: 

NaCl 9.00  gm. 

KCl 0.42  gm. 

CaCl2 0.24  gm. 

NaHCOa 0.30  gm. 

Water  to  make lOOO.OOc.c. 

For  amphibia: 

NaCl 7.00  gm. 

KCl 0.30  gm. 

CaCl2  (crystals) 0.26  gm. 

Water  to  make lOOO.OOc.c. 

3.  Locke's  Solution. — 

Same  as  Ringer's  solution  for  mammals,  to  which  has  been  added 
1.00  gms.  of  dextrose. 

4.  Tyrode's  Solution.^ — H-ion  concentration  is  0.2  x  10"^. 

NaCl 8.00  gm. 

KCl 0.20  gm. 

CaCl2 0.20  gm. 

MgCl2 •    .      .      .      .  O.lOgm. 

NaHCOs l.OOgm. 

NaH2P04 0.05  gm. 

Water  to  make lOOO.OOc.c. 

1  See  Rona  and  Neukirch,  Pfliiger's  Arch.,  1912,  cxlviii,  279. 


ANESTHESIA  29 

CARE  OF  TISSUES  AND  ANIMALS. 

In  working  with  tissues  or  with  animals  intelligent  care  is  neces- 
sary to  get  results  that  are  dependable.  Certain  things  must  be 
avoided  as  well  as  certain  conditions  fulfilled.  In  working  with 
tissues  or  isolated  organs,  therefore,  avoid: 

Stretching. 

Overheating. 

Cooling. 

H\'per-  or  hypotonic  solutions. 

Rough  manipulation  or  handling. 

Exposure  to  air,  or  drying. 
The  results  of  the  above  are  seen  especially  with  uterine,  intestinal, 
or  heart  strips.     Unless  the  technic  and  working  conditions  are 
adequate,  poor  and  distorted  results  are  obtained. 
In  working  with  animals  avoid: 

Excitement. 

Hemorrhage. 

Shock. 

Variations  in  the  depth  of  anesthesia. 

Reduced  temperature. 

Persistent  or  abnormal  sensory  stimulation. 

Too  great  voltage  to  stimulate  nerves. 
Use  all  caution  to  preserve  the  vitality  of  the  animals,  as  only 
under  such  conditions  can  dependable  and  uniform  results  be 
obtained.  It  is  highly  important  that  the  anesthesia  be  uniform. 
All  drugs  and  those  especially  that  act  on  the  nervous  system  are 
greatly  modified  by  the  depth  of  the  anesthesia,  e.  g.,  digitalis 
produces  vomiting  in  the  normal  dog,  but  not  in  the  anesthetized; 
epinephrin  will  raise  the  pressure  much  more  in  the  unanesthetized 
than  in  the  anesthetized  animal.  Anesthesia  will  stop  strychnin 
convulsions.    Many  other  examples  might  be  cited. 

ANESTHESIA. 

In  most  work  on  mammals  an  anesthetic  is  used.  The  choice 
depends  upon  the  animal  and  on  the  experiments.  Ether  and 
chloroform  are  the  most  frequently  used  and  unless  there  is  an 
objection  to  it,  1  c.c.  of  morphin  3  per  cent.  hypodermic3,lly  renders 
the  procedure  easier  and  lessens  the  amount  of  the  anesthetic 
required.  Since  anesthesia  is  the  preliminary  step  to  other  opera- 
tions, it  will  be  described  first,  although  a  demonstration  of  anes- 


30 


INTRODUCTION 


thesia  is  vastly  superior  to  any  written  description.  The  mammals 
most  used  for  laboratory  experiments  are  dogs,  cats,  guinea-pigs  and 
rabbits.  Slightly  different  technic  is  used  in  the  anesthetization 
of  each. 

General  Principle. — The  animal  may  be  held  in  any  convenient 
position,  avoiding  pain,  excitement,  injury  or  other  distracting 
circumstance. 

Small  animals  and  e^'en  dogs  may  be  enclosed  in  a  box  and  the 
anesthetic  dropped  into  the  box  through  a  funnel,  or  a  wad  of  cotton 
saturated  with  the  anesthetic  may  be  placed  in  the  box  (Fig.  1). 
^^Tieh  the  animal  is  sufficiently  anesthetized  it  may  be  removed 
and  the  anesthetic  administered  by  the  drop  method.     The  most 


Fig.  1. — Method  of  anesthetizing  dog  in  a  box. 


used  and  best  laboratory  anesthetic  is  ether.  Chloroform  may  also 
be  used  and  should  be  studied.  A  mixture  of  the  two  is  sometimes 
used,  but  it  is  not  advised.  The  following  methods  have  been  found 
convenient  for  the  usual  laboratory  animals. 

Dogs. — ^Hold  the  animal  in  the  way  illustrated  (Fig.  2).  Use  a 
towel  and  fold  to  fit  the  animal's  nose  in  the  form  of  a  cone.  Drop 
the  ether  or  chloroform  on  at  a  rate  of  about  10  drops  per  second 
and  watch  the  reflexes.  If  there  is  no  objection  to  it  the  animal 
may  be  given  a  small  hypodermic  of  morphin  before  the  ether.  A 
small  dog  may  be  given  1  c.c.  of  3  per  cent,  morphin  sulphate  and 
the  dose  repeated  in  fifteen  minutes  if  thought  advisable.  Instead 
of  using  a  towel  a  metal  cone  may  be  used.  This  may  be  prepared 
from  the  ordinary  ether  can  by  removing  the  bottom  and  connecting 


ANESTHESIA  31 

the  normal  outlet  with  an  ether  bottle.     The  diagrams  or  photo- 
graphs will  illustrate  this.    The  tests  of  good  anesthesia  are: 

1.  Loss  of  voluntary  movements. 

2.  No  cutaneous  reflexes. 

3.  Slight  corneal  reflexes  or  none  in  deep  anesthesia. 
•4.  E^'en  and  fairly  deep  respiration. 

5.  Medium  blood-pressure  and  pulse. 


Fig.  2. — Drop  method  of  anesthetizing  a  dog. 

This  sort  of  anesthesia  may  be  continued  by  giving  chloroform 
or  ether  from  a  dropping  bottle  at  regular  intervals  of  about  thirty 
seconds.  The  number  of  drops  that  each  animal  requires  can  be 
determined  by  e>rperiment ;  3  to  6  drops  every  thirty  seconds  is 
recommended.     It  is  important  to  maintain  uniform  anesthesia. 

Cats. — Ether  or  a  mixture  of  chloroform  and  ether  is  a  good 
anesthesia  for  cats.  The  easiest  method  to  use  on  cats  is  as  follows: 
Procure  a  box  of  a  size  to  hold  the  cat  conveniently.  Be  sure  that 
the  lid  fits  tightly.  Drop  into  the  box  with  the  cat  a  small  piece 
of  cotton  saturated  with  ether  or  with  a  chloroform-ether  mixture; 
10  CO.  in  broken  doses  will  anesthetize  a  cat  in  ten  minutes;  glass 
slides  in  the  box  will  permit  observation.  After  this,  proceed  as 
with  the  dog.  Pure  ether  very  easily  kills  a  cat  and  chloroform  is 
more  dangerous. 

Rabbits. — Rabbits  are  best  anesthetized  with  urethane,  2  gm. 
given  by  the  mouth.  Follow  this  with  light  and  careful  use  of  ether; 
this  is  given  in  the  same  method  as  chloroform  was  given  to  the  cat. 
Rabbits  die  very  readily  under  chloroform. 

Guinea-pigs. — (iuinea-pigs  are  anesthetized  with  pure  ether  or 
with  ether  followed  by  morphin,  0.1  to  0.2  c.c.  of  3  per  cent. 

Some  of  the  animals  should  be  anes^etized  in  the  box  and  com- 
pared with  others  anesthetized  by  the  cone  method.  In  this  way 
the  effect  of  the  ether  on  the  membranes  of  the  no.se,  etc.,  can  be 


32  INTRODUCTION 

seen.    The  animals  in  the  box  show  much  less  excitement  than  those 
which  are  anesthetized  by  the  cone  or  towel  method. 

Morphin  Ether. — Give  a  dose  of  0.01  gm.  per  kilo  (0.3  c.c.  per  kilo  of 
3  per  cent.)  morphin  sulphate  subcutaneously.  After  twenty  minutes 
anesthetize  the  animal  sufficiently  with  ether  to  permit  necessary 
operations,  such  as  insertion  of  cannulse  and  sectioning  of  nerves. 
Then  allow  the  animal  to  recover  from  the  volatile  anesthetic  for 
fifteen  minutes,  watching  closely  for  evidence  of  pain,  and  repeating 
small  doses  of  morphin  if  necessary.  An  animal  in  this  condition 
needs  practically  no  volatile  anesthetic  after  the  operation.  The 
objections  are:  (1)  the  morphin  produces  vagus  stimulation  and  an 
altered  heart  rate,  especially  if  there  is  a  small  amount  of  any  toxic 
substance  administered;  (2)  resuscitation  is  more  difficult  than 
when  a  volatile  anesthetic  is  used.  Three  per  cent,  morphin  is  used 
for  ease  of  calculation  in  case  one  wishes  to  convert  the  metric  into 
the  apothecary  system.  One  c.c.  of  3  per  cent,  is  equal  to  0.03  gm., 
which  is  equal  to  0.5  grain.  One  c.c.  of  this  solution  is  enough  for  a 
small  dog. 

INTRATRACHEAL  INSUFFLATION. 

Meltzer  has  devised  a  method  of  artificial  respiration  which  is 
specially  useful  in  resuscitation  work  and  in  operations  where  the 
chest  is  opened.  Anesthesia  can  also  be  carried  on  by  the  same 
procedure.  The  method  consists  in  driving  air  by  means  of  external 
pressure  through  a  tube  which  has  been  introduced  through  the 
mouth  and  larynx  deep  into  the  trachea.  In  animal  work  where 
the  trachea  is  exposed  the  tube  may  be  placed  directly  into  the 
trachea.  The  insufflated  air  returns  through  the  space  between  the 
tube  and  the  wall  of  the  trachea  and  escapes  through  the  mouth  and 
nose.  When  the  size  of  the  tube  and  the  rate  of  interruption  and 
the  degree  of  pressure  are  properly  selected  this  method  will  main- 
tain life  indefinitely,  even  in  curarized  animals  with  widely  open 
pneumothorax. 

The  Tube  and  Its  Introduction. — The  tube  should  be  flexible  and 
elastic.  It  should  be  sufficiently  large  to  admit  the  necessary 
amount  of  air  and  small  enough  to  permit  the  return  of  the  air 
between  the  tube  and  the  wall  of  the  trachea. 

Introduction. — The  mouth  of  a  well-narcotized  animal  should  be 
kept  open  by  means  of  a  gag,  the  tongue  pulled  out,  and  by  means 
of  a  curved  forceps  the  frenum  of  the  epiglottis  grasped  and  pulled 
back.  The  introduction  of  the  tube  into  the  larynx  is  then  a  very 
simple  matter.    Meltzer  thinks  that  this  method  may  also  be  used 


INTRA  TRACHEAL  INSUFFLA  TION 


33 


Fig.  3. — Apparatus  for  anesthesia  by  intracranial  insufflation.  By  means  of  a 
glass  blower's  foot-bellows  (B)  air  is  driven  at  will  through  a  system  of  branching 
tubes  into  the  intratracheal  tube  (hi.-T.).  The  first  branching  of  the  tubes  is 
introduced  for  the  purpose  of  regulating  the  interruption  of  the  air-stream.  From 
the  right  branch  a  tube  is  led  off  laterally,  carrying  a  stop-cock  {St.  3),  which  is  to 
be  used  for  the  interruptions  of  the  air-current.  Duri'ng  the  opening  of  the  stop- 
cock a  part  of  the  air-current  continues  through  the  left  tube,  thus  preventing  too 
great  a  reduction  of  the  pressure,  which  is  undesirable.  By  means  of  a  screw  clamp 
(S.  C.)  the  amount  of  air  which  is  to  pass  through  the  left  tube  can  be  regulated;  a 
narrowing  of  this  tube  causes  a  greater  collapse  of  the  lungs  during  the  interruption. 
The  second  branching  of  the  tubes  is  introduced  for  the  purpose  of  regulating  the 
anesthesia.  The  ether  bottle  (E)  is  interpolated  in  the  left  branch;  the  right  branch 
runs  uninterrupted  outside  of  the  bottle  to  unite  with  the  part  of  the  left  tube  which 
comes  from  the  ether  bottle.  When  the  stop-cock  in  the  right  branch  {St.  2)  is 
closed,  all  the  air  passes  through  the  ether  bottle;  when,  instead,  both  stop-cocks 
in  the  left  branch  (.S7.  /  and  St.  4)  are  closed,  only  pure  air  reaches  the  intratracheal 
tul>c,  and  when  all  three  stop-cocks  are  open  only  one-half  of  the  air  is  saturated 
with  the  anesthetic.  By  partial  closing  of  the  stop-cocks  various  degrees  of  anes- 
thesia can  be  obtained.  The  third  opening  in  the  ether  bottle  carries  a  tube  with  a 
funnel  {F)  through  which  the  bottle  is  filled  with  the  anesthetic;  the  tube  is  otherwise 
kept  tightly  closed  by  means  of  a  screw  clamp  {S.  C).  All  three  rubber  stoppers  are 
firmly  and  permanently  wired  down  to  resist  various  pressures.  When  the  ether  bot- 
tle is  to  be  refilled  during  insufflation,  both  stop-cocks  on  the  left  side  are  closed,  while 
the  one  on  the  right  side  is  open.  The  tube  which  connects  the  anesthesia  circle  of 
tubing  with  the  intratracheal  tube  {In.-T.)  carries  two  lateral  tubes;  one  is  connected 
with  a  manometer  (M),  whi(;h  needs  no  description,  and  the  other  leads  to  a  safety- 
valve  (S.  V.)  of  a  simple  construction.  To  the  ruliber  tubing  is  attached  a  graduated 
glass  tul>e,  the  lower  end  of  which  is  inmiersed  under  the  surface  of  the  mercury  in 
thi.s  l>ottle  to  a  fler>th  crjrresponding  to  the  pressure  which  is  desired  for  the  intra- 
tracheal insufflation.  For  instance,  if  the  pressure  should  be  not  more  than  20 
nini.  of  mercury,  the  glass  tube  is  immersed  just  20  mm.  lielow  the  surface  of  the 
mercury.  The  glass  tube  is  kept  in  the  desired  place  by  means  of  a  rul)i)er  ring 
resting  upon  the  opening  of  the  mercury  bottle.  This  device  gives  great  safety  to 
the  working  of  the  method.  No  matter  how  strong  and  irregular  the  bellows  is 
worked,  the  intratracheal  iires.sure  could  never  rise  above  the  one  arranged  for; 
the  surplus  of  air  escapes  through  the  tube  from  under  t  ho  iriercury.  In  this  arrange- 
ment a  wash  bottle  can  be  inserted  containing  warm  Ringer's  .solution,  wliic^h  would 
sorve  as  a  filter  as  well  as  a  source  for  heat  and  moisture.  In  our  experimental  work 
we  never  used  it  and  never  missed  it. 


34  INTRODUCTION 

in  human  surgery,  but  it  has  been  found  that  the  vocal  cords  may 
be  injured  and  that  spasm  of  the  glottis  tends  to  prevent  the  return 
of  the  air.  After  the  tube  enters  the  trachea  it  should  be  pushed 
gently  forward  until  it  meets  with  a  resistance;  the  end  of  the  tube 
is  usually  then  in  a  deep  place  in  the  right  bronchus.  The  tube 
should  be  withdrawn  then  5  or  6  cm.  (two  or  three  inches).  Some 
arrangement  should  now  be  improvised  to  keep  it  in  place  and  to 
protect  it  from  the  teeth. 

Insufflation  Apparatus. — The  figure  (Fig  3)  with  the  attached 
legend  is  self-explanatory.  This  is  Meltzer's  own  description  of 
the  apparatus. 

In  working  the  bellows,  interruption  in  the  pressure  should  be 
made  about  eight  times  per  minute.  These  need  not  be  at  abso- 
lutely regular  intervals.  The  color  of  the  mucous  membranes  will 
indicate  the  degree  of  oxygenation.  The  pressure  in  the  manometer 
should  be  watched  and  not  raised  too  high. 

The  tube  should  always  be  introduced  with  care  and  without 
force.  The  diameter  should  be  too  small  rather  than  too  large. 
There  should  be  a  safety  valve  to  prevent  the  pressure  rising  too 
high.  There  should  be  at  least  six  interruptions  per  minute.  There 
should  never  be  marked  collapse  of  the  lungs  when  the  chest  is 
opened,  because  when  they  collapse  the  walls  of  the  vesicles  tend 
to  adhere,  and  it  takes  a  dangerous  pressure  for  distention  again. 
It  requires  much  less  pressure  to  keep  the  lung  distended. 

Anesthesia  by  Insufflation. — Fig.  3  and  the  legend  is  self-explana- 
tory. If  too  much  ether  has  been  given  the  insufflation  with  pure 
air  is  the  best  cure. 


PHARYNGEAL  INSUFFLATION. 

The  following  method  also  has  been  developed  by  Dr.  S.  J. 
Meltzer,  and  is  described  in  detail  in  the  Medical  Record,  1917, 
xcii,  103,  and  in  technical  paper  77  (U.  S.  Department  of  Interior, 
Bureau  of  Mines).  The  method  was  developed  because  of  some 
disadvantages  in  the  method  of  intratracheal  insufflation  by  the  same 
author.  These  drawbacks  are  as  follows:  (1)  The  introduction  of  a 
tube  into  the  trachea  requires  some  dexterity  and  practice,  and  (2) 
the  apparatus  available  on  the  market  used  for  keeping  up  intra- 
tracheal insufflation  is  expensive.  It  is  therefore  improbable  that 
the  apparatus  and  the  experienced  operator  will  be  at  hand  in  many 
cases  when  needed.  The  method  of  intrapharyngeal  insufflation 
is  simple  and  efficient.    The  apparatus  is  seen  ready  for  use  in  Fig. 


PHARYNGEAL  INSUFFLATION 


35 


4.  Instead  of  the  bellows,  as  seen  in  the  picture,  an  oxygen  tank 
may  be  used.  Following  is  the  manufacturers'  description  and 
explanation  of  the  apparatus,  which  is  not  patented  and  rather 
inexpensive. 


Artificial  Respiration    and   Resuscitation 

~    Meltzer  Method    - 

GEO.  TIEMANNl  8r  CO NEW  YORK 


Brokea    line    shows 
stomach    tube,   in    place.. 
w/iif/i    IS  necessary  onl/ 
whert    fibdoiTunn/  pressure 
pod  (11  cciri    for  any  reason 
not    hf    uied. 


Fig.  4 


Artificial  Respiration  and  Resuscitation  by  the  Meltzer  Method. — 
The  Meltzer  method  of  artificial  respiration  is  based  upon  the  prin- 
ciple of  pharyrif/eal  iri,Hvj[Jlftti(jn ,  a  process  that  consists  in  ex])anding 
the  lungs  with  air  at  regular  intervals  of  about  twelve  to  the  minute 


36  INTRODUCTION 

and  depending  on  the  elasticity  of  the  chest  walls  to  expel  a  portion  of 
the  air  during  each  intervening  period.  In  using  the  apparatus  a 
board  is  first  strapped  tightly  over  the  abdomen,  Fig.  4  (//,  l),to 
prevent  the  stomach  instead  of  the  lungs  from  being  expanded  with 
the  air. 

The  pharyngeal  tube  attached  to  the  apparatus  is  then  placed  in 
the  mouth  and  pushed  as  far  back  as  it  will  go,  Fig.  4  {III),  and 
the  tongue  is  drawn  forward  and  tied  to  the  tube,  Fig.  4  (77,  2). 
The  tube  pushes  the  soft  palate  upward  and  effectually  closes  the 
passageway  through  the  nose.  Fig.  4  (777)  so  that  no  air  can  escape 
through  the  nostrils,  while  an  opening  in  the  bottom  of  the  tube 
permits  the  air  to  pass  freely  down  the  throat. 

For  supplying  the  air,  a  foot  bellows  is  used.  Fig.  4  (7,  4)-  As  the 
air  is  conducted  through  the  tube  it  passes  a  valve  (3)  which  regulates 
the  inspiration  and  expiration.  With  watch  in  hand,  or  in  synchro- 
nism with  his  own  respiration,  the  attendant  turns  the  ring  that 
governs  this  valve  alternately  to  the  right  and  left  at  regular 
intervals. 

When  the  ring  is  turned  to  the  right  the  air  is  forced  into  the  lungs, 
and  when  the  ring  is  turned  to  the  left  the  air  is  shut  off,  at  the 
same  time  a  small  vent  is  opened  and  the  air  escapes  from  the  lungs. 
Just  below  this  valve  is  another  valve  for  regulating  the  pressure 
of  the  air  given  the  patient,  Fig.  4  (7,  77,  5). 

At  the  start  the  pressure  used  is  very  low,  but  is  increased  by 
gradual  closing  of  the  valve,  until  the  chest  shows  a  regular  normal 
heaving. 

In  case  the  apparatus  is  hurriedly  called  into  use  during  an  abdom- 
inal operation,  in  which  case  the  abdominal  board  (1)  cannot  be 
strapped  on,  a  stomach  tube  is  passed  through  the  pharyngeal  tube, 
through  the  esophagus  and  into  the  stomach,  Fig.  4  (777). 

An  important  feature  of  the  apparatus  is  that  it  can  be  operated 
by  one  man,  who  need  not  be  an  expert.  The  bellows  is  worked  by 
the  foot  and  the  respiratory  valve  is  operated  by  the  right  hand, 
leaving  the  left  hand  free  for  making  any  adjustments  that  may  be 
necessary. 

Parts  Composing  Meltzer's  Device  for  Artificial  Respiration  by 
Pharyngeal  Insufflation. — 1.  Abdominal  pressure  pad. 

2.  Pharyngeal  tube. 

3.  Respiratory  Valve. 

4.  Foot  bellows. 

5.  T-tube  with  a  screw  clamp,  interpolated  between  the  respira- 
tory valve  and  the  foot  bellows.     Pharyngeal   tube,    respiratory 


PHARYNGEAL  INSUFFLATION  37 

valve,  T-tube  and  foot  bellows  should  be  kept  connected  by  means 
of  good  rubber  tubing  which  does  not  kink.  The  apparatus  will 
then  be  in  readiness  for  immediate  application. 

6.  Air  bag  to  give  uniform  flow  of  air. 

7.  Tongue  forceps  and  tape  (or  gauze  bandage)  for  tying  the 
tongue  to  the  pharyngeal  tube. 

8.  Stomach  tube  fitting  into  the  opening  of  the  pharyngeal 
tube  to  be  used  for  the  escape  of  surplus  air  from  the  stomach  in 
cases  where  no  pressure  can  be  exerted  upon  the  abdomen. 

Order  of  Procedure. — 1.  The  pressure  pad  is  applied  to  the  abdo- 
men. 

2.  Tongue  drawn  out. 

3.  Pharyngeal  tube  is  inserted  into  the  mouth  until  it  reaches 
the  posterior  wall  of  the  pharynx  and  then  the  drawn  out  tongue  is 
tied  to  the  pharyngeal  tube.  This  will  keep  the  epiglottis  raised 
and  the  tube  in  its  proper  place. 

4.  An  assistant  operates  the  bellows  while  he  takes  the  respira- 
tory valve  in  his  hand  and  moves  the  ring  from  side  to  side  by  the 
thumb,  synchronically  with  his  own  respirations. 

5.  The  screw  clamp  on  the  T-tube  is  immediately  screwed  down 
until  the  chest  shows  a  proper  heaving. 

The  heaving  of  the  chest  need  not  be  too  strong.  A  satisfactory 
number  of  respirations  should  be  established  twelve  to  fifteen  per 
minute.  If  the  air  tends  to  accumulate  in  the  stomach,  or  in  cases 
in  which  the  abdomen  is  open  and  the  board  cannot  be  applied  a 
stomach  tube  is  inserted.  The  air  escapes  through  and  around  the 
tube.  Details  of  the  procedure  and  its  application  to  clinical 
problems  are  given  clearly  in  the  references. 

The  Schafer  Method  of  Artificial  Respiration  and  Resuscitation. — 
This  method  was  devised  by  Dr.  E.  A.  wSchiifer,  Professor  of  Physio- 
logy in  the  University  of  Edinburgh.  He  recommends  that  the 
patient  be  placed  in  a  prone  position  with  the  head  slightly  lower 
than  the  body.  The  physician  or  operator  is  astride  or  to  the  side 
of  the  patient,  and  the  open  hands  are  placed  on  the  patient's  side 
at  the  level  of  the  lower  ribs,  and  firm  but  not  too  violent  pressure 
is  applied.  This  is  done  by  allowing  the  weight  of  the  operator  to 
come  on  the  arms.  After  this  pressure  has  been  a])])lie(l  for  about 
three  seconds  (Fig.  5,  a)  the  pressure  is  relaxed  by  raising  the  body 
(Fig,  5,  h).  The  pressure  and  relaxation  should  be  made  about 
twelve  times  a  minute;  the  amount  of  air  entering  the  hmgs  under 
these  conditions  is  as  mu(;h  as  or  more  tlian  in  onhnary  resj)irati()n. 

lie  found  that  in  a  normal  jxTson  tlie  anionnt  of  air  exchanged 


38  INTRODUCTION 

in  a  minute  is  about  585  c.c.  when  the  respirations  are  thirteen 
times  a  minute,  or  an  average  of  450  c.c.  of  tidal  air  at  each  breath. 
With  his  method  of  artificial  respiration  he  was  able  to  pump 
6760  c.c.  through  the  lungs  in  a  minute;  when  compared  with  other 
methods  of  respiration  he  found  this  method  the  most  efficient. 


Fig.  5. — Schafer's  prone-pressure  method  of  artificial  respiration, 
applied;  h,  pressure  removed. 


a,  pressure  being 


The  advantages  of  the  method  are: 

1.  It  is  fully  efiicient. 

2.  It  can  be  performed  without  fatigue  by  a  single  individual. 

3.  It  is  simple  and  easily  learned. 

4.  It  allows  the  tongue  to  fall  forward  and  the  mucus  and  water 
to  escape  from  the  mouth,  so  that  the  tendency  of  these  to  block 
the  passage  of  air  which  is  inherent  to  the  supine  position  is  alto- 
gether obviated. 

Other  methods  of  artificial  respiration  may  be  mentioned,  but 
they  are  of  historical  interest  only :    They  are : 


THE  THIRD  RESUSCITATION  COMMISSION  39 

The  Marshall  Hall  Method. — The  IMarshall  Hall  method  consists 
of  rolling  the  patient  alternately  from  the  prone  position  to  the 
lateral  position  and  pressing  between  the  shoulder-blades  when  he 
is  in  the  prone  position.  Schafer  found  that  by  this  method  the 
tidal  air  volume  was  254  c.c.  as  against  520  c.c.  for  his  own  method, 
or  3300  c.c.  per  minute  as  against  6760  c.c. 

The  Sylvester  Method. — In  this  method  the  patient  lies  on  his 
back,  with  the  shoulders  raised  and  the  head  hanging  low.  The 
operator  takes  hold  of  the  patient's  arms  above  the  elbow  and 
raises  them  away  from  the  body  until  they  arrive  at  about  above 
the  patient's  head.  This  raises  the  ribs  and  increases  the  capacity 
of  the  chest.  The  arms  are  then  lowered  by  his  side  and  the  elbows 
flexed  and  pressed  against  the  lower  part  of  the  chest.  This  dimin- 
ishes the  air-holding  capacity  of  the  chest  by  driving  the  air  out. 
The  tongue  is  likely  to  fall  back  into  the  throat  and  impede  respira- 
tion unless  someone  grasps  it  and  pulls  it  forward. 

The  tidal  air  by  this  method  Schafer  found  to  be  only  175  c.c. 
and  the  air  exchanged  a  minute  only  2280  c.c.  as  against  520  c.c, 
and  6760  c.c.  respectively  for  his  own  method.  Other  methods 
were  investigated  by  Schafer  and  by  the  recent  National  Com- 
mittee, who  corroborated  Schafer' s  findings. 

The  Third  Resuscitation  Commission. 

The  subject  of  resuscitation  is  so  important  that  we  cannot  do 
better  than  include  a  report  of  the  Third  Resuscitation  Commission, 
which  explains  itself,  and  which  shows  the  importance  of  the  subject 
in  Medicine. 

To  save  space  we  have  eliminated  some  non-essential  matter 
from  the  report  which  is  complete  in  Science,  December  6,  1918, 
p.  563. 

The  commission  included  leading  investigators  in  physiology, 
pharmacology,  medicine,  surgery  and  engineering,  administrative 
officers  of  Army,  Navy  and  Public  Health  Services,  and  finally 
representatives  from  the  larger  electrical  companies  where  the 
problems  of  resuscitation  have  to  be  dealt  with  daily.  As  originally 
constituted  it  consisted  of  fifteen  men.  Later  four  others  were 
added  in  an  advisory  capacity.' 

•  There  were  present  at  the  meeting:  Past  Assistant  Surgeon  E.  F.  Du  Bois, 
U.B.N. R.F.,  of  the  Hurcau  of  Meflicino  and  Surgery,  Navy  Department;  Dr.  D.  L. 
Edsall,  Professor  of  Medicine  and  Doan  of  Harvard  Medical  Sciiool;  Mr.  W.  C.  L. 
Eglin,  Chairman  of  Committee  on  Safely  Rules  and  Accident  Prevention  of  the 
National  Electric  Light  Association;  Dr.  Yandell  Henderson,  Professor  of  Physiol- 


40  INTRODUCTION 

The  practical  difficulties  in  life-saving  problems  are  these: 

A  mechanical  life-saving  device  is  not  immediately  available, 
the  possession  of  such  an  apparatus  gives  a  false  sense  of  security, 
'^6  that  life-guards,  policemen,  medical  students  and  even  hospital 
physicians  are  not  adequately  trained  in  either  handling  the  appa- 
ratus or  the  manual  methods. 

In  view  of  these  facts  the  committee  advised  that  the  prone- 
pressure  method  of  Schafer  is  preferable  to  any  other  manual  method. 
Instruction  in  this  method  should  be  included  in  the  training  of  all 
people  likely  to  handle  this  class  of  cases.  When  such  an  emergency 
arises  the  manual  method  is  to  be  applied  at  once  and  continued 
during  the  transportation  of  the  individual  to  hospitals  or  first-aid 
stations.  Efforts  on  resuscitation  should  be  continued  until  spon- 
taneous breathing  is  permanently  established.  This  means  that 
patients  must  be  watched  for  a  definite  period  after  respiration  is 
established.  In  the  absence  of  all  signs  of  life  the  method  is  not  to  be 
abandoned  until  after  an  hour's  trial.  It  is  not  to  be  used  in  cases  of 
coma  where  normal  respiration  continues.  In  cases  of  gas  asphyxia 
the  simultaneous  administration  of  oxygen  is  advised. 

During  all  stages  of  resuscitation  the  body  heat  is  to  be  main- 
tained. 

Mechanical  devices  should  be  confined  to  hospitals  and  institu- 
tions. They  should  be  investigated  further  with  a  view  to  their 
perfection. 

Fourteen  members  agreed  to  the  above  report.  Henderson  took 
the  stand  that  really  efficient  and  reliable  devices  existed  already, 

ogy,  Yale  University,  and  Consulting  Physiologist  of  the  Bureau  of  Mines;  Dr. 
William  H.  Howell,  Professor  of  Physiology  and  Assistant  Director  of  the  School  of 
Hygiene  and  Public  Health,  Johns  Hopkins  University,  Member  of  the  National 
Academy  of  Sciences;  Dr.  Reid  Hunt,  Professor  of  Pharmacology,  Harvard  Medical 
School  and  Secretary  of  the  Commission;  Prof.  A.  E.  Kennelly,  Professor  of  Electri- 
cal Engineering  at  Harvard  University  and  the  Massachusetts  Institute  of  Tech- 
nology; Dr.  Charles  A.  Lauffer,  Medical  Director  of  the  Westinghouse  Electric 
Company,  Pittsburgh,  Pa.;  Dr.  S.  J.  Meltzer,  Rockefeller  Institute,  Chairman  of 
the  Commission  and  Member  of  the  National  Academy  of  Sciences;  Dr.  Joseph 
Schereschewsky,  Assistant  Surgeon-General,  U.  S.  Public  Health  Service;  Dr.  G. 
N.  Stewart,  Professor  of  Experimental  Medicine,  Westei;n  Reserve  University, 
Cleveland;  Prof.  Elihu  Thomson,  Gt\neral  Electric  Company,  West  Lynn,  Mass., 
Member  of  the  National  Academy  of  Sciences;  Lieut-Col.  Edward  B.  Vedder,  of 
the  Army  Medical  School;  Major  Frank  G.  Young,  of  the  Ordnance  DiAasion  of 
the  War  Department. 

A  telegram  was  received  from  Surgeon-General  Gorgas  that  Dr.  Charles  H. 
Frazier,  Professor  of  Surgery,  University  of  Pennsylvania,  is  to  represent  his  office. 
(In  a  subsequent  communication.  Major  Frazier  accepted  his  appointment.)  Con- 
ferees: Mr.  P.  H.  Bartlett,  Philadelphia  Electric  Company;  Mr.  Wills  Maclachlan, 
Electrical  Employers'  Association,  Toronto,  Canada;  Mr.  C.  B.  Scott,  Chairman 
of  the  Subcommittee  on  Accident  Prevention  National  Electric  Light  Association; 
Dr.  F.  E.  Schubmehl,  General  Electric  Company,  West  Lynn,  Mass. 


RESOLUTIONS  ADOPTED  BY  THE  COMMISSION  41 

but  that  their  results  were  inferior  to  manual  methods  and  that  they 
actually  contribute  to  decrease  in  life  saving,  because  of  the  false 
assurance  they  give.  He  felt  that  they  should  all  be  abandoned  in 
favor  of  the  manual  prone- pressure  method. 

Resolutions  Adopted  by  the  Commission. 

In  the  discussion  following  the  presentation  of  methods  and 
evidence  to  the  commission  the  following  important  facts  were 
emphasized: 

1.  That  in  most  accident  cases  no  resuscitation  apparatus  is  at 

hand  for  immediate  use. 

2.  That  reliance  upon  the  use  of  special  apparatus  diminishes 
greatly  the  tendency  to  train  persons  in  the  manual  methods  and 
discourages  the  prompt  and  persevering  use  of  such  methods. 

3.  That  police  officers  or  physicians  often  interfere  with  the 
proper  execution  of  manual  methods,  in  that  they  direct  that  the 
patient  be  removed  in  an  ambulance  to  some  hospital,  thus  inter- 
rupting the  continuance  of  artificial  respiration. 

4.  That  in  many  hospitals  the  members  of  the  staff  are  not  all 
acquainted  with  the  methods  of  artificial  respiration. 

5.  That  in  medical  schools  instruction  is  not  properly  provided 
for  students  in  the  manual  methods  of  artificial  respiration. 

In  view  of  these  facts  the  following  resolutions  were  adopted  by 
the  commission: 

1.  The  prone-pressure,  or  Schafer,  method  of  resuscitation  is 
preferable  to  any  of  the  other  manual  methods. 

2.  Medical  schools,  hospitals,  fire  and  police  departments,  the 
Army  and  Navy,  first-aid  associations  and  industrial  establish- 
ments in  general  should  be  urged  to  give  instruction  in  the  use  of 
the  prone-pressure  method  of  resuscitation. 

3.  Individuals  who,  from  accident  or  any  other  cause,  are  in  need 
of  artificial  respiration  should  be  given  manual  treatment  by  the 
prone-pressure  method  immediately  on  the  spot  where  they  are 
found.  It  is  all-important  that  this  aid  be  rendered  at  once.  The 
delay  incident  to  removal  to  a  hos])ital  or  elsewhere  may  be  fatal, 
and  is  justifiable  only  when  there  is  no  one  at  hand  competent  to 
give  artificial  resi)iration.  If  complications  exist  or  arise,  which 
require  hospital  treatment,  artificial  respiration  should  be  main- 
tained in  transit,  and  after  arri\  al  at  the  hospital,  until  spontaneous 
respirations  begin. 

4.  Persons  receiving  artificial  rcsjMration  should,  as  much  as 
possible,   be   kept   warm    and    llic   artificial    respiration    should    be 


42  INTRODUCTION 

maintained  until  spontaneous  breathing  has  been  permanently 
restored,  or  as  long  as  signs  of  life  are  present.  Even  in  cases  in 
which  there  is  no  sign  of  returning  animation,  artificial  respiration 
should  be  kept  up  for  an  hour  or  more. 

5.  A  brief  return  of  spontaneous  respiration  is  not  a  certain 
indication  for  terminating  the  treatment.  Not  infrequently  the 
patient  after  a  temporary  recovery  of  respiration  stops  breathing 
again.  The  patient  must  be  watched,  and  if  normal  breathing 
stops,  the  artificial  respiration  should  be  resumed  at  once. 

6.  Artificial  respiration  is  required  only  when  natural  respiration 
has  ceased.  In  cases  of  simple  unconsciousness  from  any  cause  in 
which  natural  respiration  continues,  artificial  respiration  should 
not  be  employed  without  medical  advice. 

7.  The  commission  recommends  that  in  cases  of  gas  asphyxia- 
tion, artificial  respiration,  whether  given  by  a  manual  method  or 
by  special  apparatus,  should  be  combined,  when  possible,  with  the 
inhalation  of  oxygen  from  properly  constructed  apparatus. 

8.  With  regard  to  the  employment  of  mechanical  devices  for 
artificial  respiration  the  commission  feels  that  it  ought  not  at 
present  to  take  a  definite  stand  either  for  or  against  any  particular 
form  of  apparatus.  However,  the  commission  recommends,  that 
the  use  and  installation  of  apparatus  should  be  confined,  for  the 
present,  to  properly  equipped  institutions  under  medical  direction. 
The  commission  recognizes  the  great  need  of  simple  devices  capable 
of  performing  artificial  respiration  reliably  and  efficiently.  It 
therefore  recommends  a  careful  study  of  the  problem,  directed 
toward  the  development  of  a  reliable  method  appropriate  for  general 
adoption.  Such  studies  can  best  be  carried  on  in  properly  equipped 
hospitals  and  laboratories  which  offer  opportunities  and  facilities 
for  critical  observation  and  experimentation. 

In  view  of  the  importance  which  the  knowledge  of  proper  methods 
of  resuscitation  possesses  for  public  health  and  safety,  and  consider- 
ing the  fact  that  many  practitioners,  members  of  hospital  staffs 
and  graduates  of  medicine  are  not  thoroughly  familiar  with  the 
methods  of  resuscitation,  especially  that  of  the  prone-pressure 
method,  the  commission  recommends: 

(a)  That  medical  journals  (and  other  scientific  and  practical 
journals  which  are  interested  in  the  problem  of  resuscitation)  be 
asked  to  publish  the  resolutions  adopted  by  the  commission. 

(6)  That  a  copy  of  these  resolutions  be  sent  to  the  medical  col- 
leges with  a  request  that  proper  instruction  in  this  subject  shall  be 
arranged  for  in  the  college  schedules. 


RESOLUTIONS  ADOPTED  BY  THE  COMMISSION  43 

(c)  That  these  resohitions  be  sent  to  as  many  hospitals  as  pos- 
sible, with  the  recommendation  that  members  of  the  house  staff 
shall  familiarize  themselves  with  the  methods  of  resuscitation. 

(d)  In  order  that  the  resolutions  of  the  commission  may  be 
brought  to  the  attention  of  interested  circles  (fire  and  police  depart- 
ments, industrial  plants,  etc.)  it  was  agreed  that  they  be  com- 
municated to  the  Associated  Press  (by  the  National  Electric  Light 
Association). 


CHAPTER   I. 
MODES  OF  ADMINISTERING  DRUGS. 

Frogs. — Drugs  are  usually  injected  into  the  anterior  or  posterior 
lymph  sac.  Since  these  beat  rhythmically  a  quick  entrance  into  the 
circulation  is  assured.  The  best  method  is  to  introduce  a  hypodermic 
needle  through  the  floor  of  the  mouth  and  down  into  the  anterior 
lymph  sac.  Direct  injection  into  the  lymph  sac  may  be  followed 
by  a  leakage  through  the  needle  hole,  consequently  it  is  a  less 
accurate  method.  By  going  through  the  mouth  there  is  little  likeli- 
hood of  this  error.  Demonstrations  of  each  method  should  be  given. 
See  Fig.  25,  p.  112. 

Mammals. — ^The  methods  used  are:  (1)  By  mouth;  (2)  subcu- 
taneously;  (3)  intramuscularly;  (4)  intravenously;  (5)  intraperi- 
toneally;  (6)  by  rectum;  (7)  intraspinally  or  subdurally. 

1.  By  Mouth. — ^When  the  volume  is  small  the  drugs  may  be 
given  conveniently  in  a  capsule.  The  animal's  mouth  is  held  open, 
the  head  back  and  the  capsule  thrown  back  or  placed  far  back  on 
the  tongue.  Hold  the  animal's  mouth  shut,  and  if  he  does  not 
swallow  it  spontaneously  slap  the  throat  gently  or  rub  it  toward 
the  stomach.  There  is  usually  no  trouble  to  get  the  animal  to 
swallow.     Fig.  31,  p.  134. 

The  liquids  are  most  conveniently  given  by  stomach  tube.  Hold 
the  animal  firmly;  open  his  mouth  and  insert  an  appropriate  wooden 
gag,  with  a  hole  in  it,  behind  the  molar  teeth.  Introduce  a  gum- 
elastic  catheter  through  the  hole  of  the  gag  and  push  it  into  the 
stomach.  Pour  the  liquid  through  the  tube  by  means  of  a  funnel. 
It  is  unnecessary  to  state  that  the  tube  may,  in  some  cases,  enter 
the  lungs  instead  of  the  stomach.  This  may  be  ascertained  by 
listening  for  respiration.  If  the  tube  is  in  the  trachea,  respiration 
is  heard  through  it.  In  such  cases,  withdraw  and  reinsert.  By 
pulling  the  tongue  forward  one  may  see  the  tube  in  the  proper 
location  (Figs.  6  and  7).  A  demonstration  of  the  serious  conse- 
quences of  putting  fluid  in  the  lungs  is  valuable. 

2.  Hypodermic  Injection. — Hold  the  skin  between  the  fingers 
and  with  a  quick,  firm  thrust  insert  the  needle.  Since  the  dog's 
skin  is  thick  and  the  animal  will  move,  if  not  held  carefully,  care 
must  be  taken  not  to  break  the  needle. 


MAMMALS 


45 


Fig.  6. — Method  of  introducing  liquid  into  the  stomach  of  a  rabbit. 


ViQ.  7. — Method  of  introducing  liquid  into  the  stomacli  of  a  dog. 


46  ■  MODES  OF  ADMINISTERING  DRUGS 

3.  Intramuscular  Injections.— This  may  be  made  into  any  large 
muscle;  a  quick  thrust  into  the  middle  of  the  muscle  is  best. 

4.  Intraperitoneal  Injection. — This  is  an  excellent  method  when 
large  volumes  are  to  be  injected.  Grasp  a  fold  of  the  skin  and 
muscle  of  the  flank  or  along  the  linea  alba  and  inject  perpendicularly. 

5-  Intravenous  Injections. — (a)  This  may  be  done  in  unanes- 
thetized  animals  by  pressing  the  leg  or  jugular  regions  until  the 
veins  stand  out;  then  the  needle  can  be  readily  introduced. 

(b)  When  large  volumes  are  to  be  introduced  it  may  be  well  to 
insert  a  cannula  in  the  vein  and  attach  a  burette,  with  saline  solu- 
tion, by  means  of  a  rubber  tube.  Injections  may  then  be  made  into 
the  tube  and  washed  in  from  the  burette. 


Fig.  8. — Method  of  introducing  needle  into  the  fourth  ventricle. 

(c)  In  case  of  rabbits  the  ear  vein  is  used.  The  injection  may 
be  facilitated  by  shaving  the  ear  and  rubbing  it  with  toluol  or  some 
irritating  drug.  A  clip  attached  centrally  will  make  the  peripheral 
bloodvessels  stand  out  so  that  injection  may  easily  be  made. 

6.  Intraspinally,  Suhdurally,  or  into  the  Fourth  Ventricle. — To 
inject  the  fourth  ventricle,  this  at  first  should  be  done  on  an  anes- 
thetized animal.  After  the  technic  has  been  obtained  it  is  easily 
carried  out  without  an  anesthetic,  and  causes  but  slight  pain.  Flex 
the  head  of  the  animal  strongly  on  its  chest.  Insert  a  thin  needle 
between  the  occiput  and  axis.  Point  toward  the  nose  of  the  animal 
in  the  flexed  position.  When  the  needle  has  entered  the  ventricle,  a 
clear  fluid  escapes  freely  (Fig.  8). 


OPERATIVE  TECH  NIC  47 

Injections  into  the  subdural  spinal  region  are  made  by  passing 
the  needle  along  the  side  groove  of  the  vertebra,  keeping  in  the 
straight  line  as  much  as  possible.  Done  this  way,  an  entrance 
between  the  vertebra  can  be  made.  This  should  first  be  shown  on 
the  skeleton. 

7.  Rectal  Injections.— These  are  made  through  a  catheter.  When 
the  desired  amount  of  fluid  is  introduced  a  clamp  or  forceps  may 
be  applied  to  keep  it  from  being  expelled.  If  the  drug  is  irritating 
it  should  be  mixed  with  gum  acacia,  6  per  cent.,  or  some  other  col- 
loidal material.    This  will  lessen  the  irritation. 

OPERATIVE  TECHNIC. 

Students  in  pharmacology  have  already  had  a  course  in  physio- 
logy, so  that  it  is  unnecessary  to  detail  operative  technic.  If  this 
is  done  it  is  so  voluminous  that  it  detracts  from  the  object  of  the 
experiment.  If  such  a  course  is  needed  a  few  minutes  of  demon- 
stration is  worth  hours  of  reading.  For  these  reasons  principles 
only  are  given. 

Exposure  of  Nerves, — Determine  the  approximate  position  of  the 
nerve  to  be  exposed.  Make  the  superficial  incision  about  three 
times  as  long  as  the  nerve  is  below  the  surface.  Work  mainly  by 
blunt  dissection,  but  avoid  hemorrhage  by  ligating  or  clamping 
bleeding  vessels.  Do  not  let  the  nerve  become  dry.  Keep  it  moist 
with  a  saline  or  with  the  body  fluids.  Keep  it  covered  with  the 
tissues  as  much  as  possible.  If  necessary  to  pass  a  ligature  to 
raise  it  for  stimulation,  use  linen  or  gauze  strips.  For  very  small 
nerves,  silk  threads  are  better. 

Stimulation  of  Nerves. — This  is  done  most  conveniently  in  experi- 
mental work  by  means  of  electrodes;  salts,  etc.,  may  also  stimulate. 
Never  stretch  or  pinch  a  nerve.  Do  not  let  it  become  dry,  but  keep 
it  moist  with  i)hysiological  saline.  Do  not  use  a  current  strong 
enough  to  burn  the  nerve.  No  current  should  be  used  on  a  nerve 
that  is  decidedly  unpleasant  when  held  to  the  tongue. 

Placing  a  Cannula  in  the  Trachea.— The  animal  is  placed  in  posi- 
tion on  the  operating  table  and  tied  securely,  with  head  extended 
and  throat  exposed.  Make  a  deep  median  incision  at  one  cut, 
through  the  skin,  muscles,  etc.,  down  to  the  trachea  with  the  face 
of  the  knife.  Do  not  pick  at  it,  but  cut  with  decided  intent.  When 
such  a  cut  is  made,  place  the  index  fingers  in  it  and  pull  the  fascia 
apart.  In  this  way  the  trachea,  nerves  and  vessels  may  be  exposed 
clearly  and  without  bleeding.     In  some  instances  where  a  goitre 


48 


MODES  OF  ADMINISTERING  DRUGS 


lies  in  the  field  of  operation,  special  precautions  must  be  taken  to 
stop  hemorrhage.  The  objects  of  placing  a  cannula  in  the  trachea 
are: 

1.  To  render  easier  the  process  of  anesthesia. 

2.  To  permit  artificial  respiration. 

3.  To  facilitate  resuscitation  in  cases  of  accident. 


Fig.  9. — The  most  important  anatomical  structures  in  the  dog's  neck.  1,  can- 
nula in  the  trachea;  2,  three-way  cannula  in  the  carotid  artery;  S,  trachea;  4>  5, 
vagosympathetic  nerve;  6,  thyroid  gland;  7,  rubber  tube  from  the  cannula  to  the 
pressure  bottle;  8,  rubber  tube  leading  to  the  mercury  manometer. 


A  tracheal  cannula  is  never  inserted  in  animals  which  are  to  be 
kept  after  the  operation. 

To  place  cannulse  in  veins,  arteries,  ducts,  etc.,  little  need 
be  said.  A  knowledge  of  the  anatomy  of  the  region  is  important 
and  must  be  gained  by  dissection  and  practice,  and  this  is  one  of  the 
beneficial  results  of  a  laboratory  course.    The  object  of  such  cannu- 


OPERATIVE  TECH  NIC  49 

lation  is  the  obtaining  of  records  of  blood  flow,  salivary  secretion 
and  the  like.  Cannulte  are  placed  in  veins  for  the  injection  of  fluids. 
This  cannot  always  be  easily  accomplished  by  means  of  hypodermic, 
because  in  cases  of  collapse  the  veins  of  small  animals  are  in  many 
cases  invisible.  When  a  cannula  is  inserted,  and  this  may  be 
attached  to  a  burette  with  a  rubber  tube,  injections  can  be  made 
into  the  rubber  tube,  and  the  pressure  from  the  burette  will  carry 
it  into  the  xe'm  exen  when  the  heart  is  feeble  or  stopped. 

Injecting  into  a  Vein.  —  Fill  a  burette  with  salt  solution  (all 
solutions  injected  should  be  about  40°  C.)  Attach  a  rubber  tube, 
with  pinch-cock  or  screw  clamp,  to  the  lower  end  of  it,  if  there  is  not 
a  glass  stop-cock  on  it.  The  burette  should  then  be  filled  with  0.9 
per  cent.  NaCl  solution,  as  also  the  tube.  Make  a  longitudinal 
incision  about  two  inches  long  on  the  skin  over  the  anterior  surfaces 
of  the  thigh,  near  the  middle  of  Poupart's  ligament,  to  expose  the 
femoral  vein;  the  artery  can  be  felt  through  the  intact  skin.  Blunt 
dissection  with  the  handle  of  the  knife  in  Scarpa's  triangle  will 
expose  the  vein;  place  two  ligatures  about  it  as  in  placing  the  carotid 
cannula.  Then  pick  out  a  cannula  of  the  proper  size,  allowing  for 
more  shrinkage  of  the  vein  than  of  the  artery.  The  distal  ligature 
should  then  be  tied,  the  vein  cut,  the  cannula  introduced  and 
tied  in  place.  Then  fill  it  with  0.9  per  cent.  NaCl  and  connect 
with  the  rubber  tube  on  the  burette.  (If  any  considerable  volume 
is  to  be  injected  it  should  be  at  body  temperature.)  Be  sure 
that  all  air  bubbles  have  been  carried  out  by  the  liquid.  Drugs 
can  be  injected  by  a  syringe  through  the  walls  of  the  rubber  tube 
obliquely  and  the  solution  carried  into  the  vein  by  letting  in  a  little 
salt  solution. 

Inserting  a  Cannula  into  the  Carotid  Artery. — Find  the  artery  in 
the  trough  outside  and  behind  the  muscles  covering  the  trachea. 
The  vagus  nerve,  which  is  in  the  same  sheath,  appears  white;  the 
internal  jugular  vein  is  bluish  purple  and  the  artery,  light  bluish 
or  pink.  Separate  it  entirely  from  the  surrounding  structures  by 
blunt  dissection  for  about  an  inch  and  a  half ;  be  careful  not  to  injure 
the  vagus  nerve.  Put  two  ligatures  around  the  artery,  one  below 
and  one  above  where  the  cannula  is  to  be  inserted.  The  upper  one 
is  to  be  tied  tightly.  vSelect  a  cannula  whose  diameter  is  almost 
equal  to  that  of  the  artery.  Put  a  pair  of  bulldog  forceps  on  the 
artery  just  below  the  cannula.  Make  a  small  incision  about  half- 
way through  the  diameter  of  the  artery  into  the  lumen  of  the  artery. 
'J'akc  hold  of  the  lower  end  of  the  incision  with  a  i)air  of  fine  forceps 
and  iiis(.Tt  the  cainmla  with  the  projecting  end  of  the  beveled  tip 
4 


50  MODES  OF  ADMINISTERING  DRUGS 

toward  the  forceps.  Put  the  cannula  into  place  and  fasten  it  with 
the  ligature. 

Opening  the  Thoracic  Cavity. — The  thoracic  cavity  is  opened  to 
study  the  heart  and  lungs.  To  do  this  the  breastplate  is  removed 
to  such  a  degree  that  observations  and  manipulations  may  be 
made.  The  main  points  to  watch  in  this  operation  is  not  to  injure 
the  lungs,  and  to  tie  the  large  vessels  either  before  they  are  severed 
or  to  ligate  them  quickly  if  they  are  bleeding.  The  whole  technic 
has  these  objects  in  mind.  Otherwise  the  method  of  work  has  little 
meaning.  Insert  a  tracheal  cannula  and  see  that  the  ether  bottle 
and  accompanying  apparatus  are  all  ready  for  immediate  use  before 
work  is  started.  Have  a  number  of  hemostats  ready.  Dissect 
along  the  midline  of  the  neck  down  to  the  manubrium  sterni,  using 
blunt  dissection  as  much  as  possible.  On  each  side  of  the  midline, 
make  an  incision  through  the  skin;  also  one  an  inch  from  the  midline 
for  the  entire  length  of  the  sternum.  Use  blunt  dissection  and  expose 
the  first  rib  on  each  side  and  begin  artificial  respiration.  In  the 
first  right  interspace  insert  an  aneurysm  needle  and  turn  the  handle 
so  that  the  hook  is  upward  and  embraces  the  first  rib.  Pull  it  up. 
Then  cut  it  through  with  bone  forceps  and  enlarge  the  opening.  Be 
sure  that  the  lung  is  expanding  so  that  the  tip  is  close  to,  but  is  not 
protruding  from  the  opening  in  the  chest  wall.  Be  sure  also  there  is 
good  lung  ventilation.  Just  exposed  by  the  opening,  at  the  margin 
of  the  anterior  mediastinum,  will  be  found  the  right  internal  mam- 
mary artery;  place  a  clamp  about  it.  Expose  and  clamp  the  left 
internal  mammary  artery  also.  With  scissors,  cut  through  the 
muscles  covering  the  right  side  of  the  chest  and  through  all  the 
right  ribs  with  bone  forceps  and  scissors,  using  hemostats  on  all 
the  bleeding  parts.  If  the  index  finger  is  inserted  into  the  thoracic 
cavity  and  used  as  a  guide,  cutting  into  the  lung  may  be  avoided. 
The  sternum  may  be  cut  through  with  bone  forceps.  Hemostats 
will  be  required  to  clamp  bleeding-points,  which  are  always  found 
at  the  site  of  the  internal  epigastric  vessels  near  the  lower  end  of 
the  sternum. 

The  chest  is  more  easily  opened  and  the  contents  exposed  with  less 
bleeding  by  a  midline  incision;  but  in  this  case  there  is  little  room 
for  work  within  the  chest  since  it  is  hard  to  hold  the  walls  back  and 
give  room  for  such  instruments  as  the  my  ©cardiograph.  Some 
workers,  however,  prefer  the  midline  incision,  and  if  the  attempt 
is  made  to  preserve  the  animal  after  such  an  operation,  this  is  the 
only  method  applicable. 


TO  RECORD  BLOOD-PRESSURE  IN  MAMMALS 


51 


RECORDING  BLOOD-PRESSURE  IN  MAMMALS. 

No  one  method  of  recording  blood-pressure  is  satisfactory  to 
all  experimenters.  The  technic  varies  with  the  facilities  of  the 
laboratory.  If  the  student  has  become  familiar  with  any  of  the 
usual  methods  he  will  find  it  adequate.  All  methods  depend  upon 
the  same  principle,  namely,  the  insertion  of  a  cannula  in  an  artery 
and  the  transmission  of  the  arterial  pressure  to  a  recording  instru- 
ment or  manometer. 


Fig.  10. — Apparatus  for  direct  measurement  of  blood-pressure.     -4,  3-way   cannula 
for  insertion  into  artery;  B,  valves  to  regulate  pressure;  C,  pre.ssure  bottle. 

To  measure  the  pressure  etherize  the  animal  in  the  usual  way 
and  insert  a  tracheal  cannula.  The  tracheal  cannula  is  convenient 
though  not  absolutely  necessary.  It  gives  a  more  perfect  control  of 
the  animal  and  artificial '  respiration  can  be  given  at  any  time, 
should  it  be  needed.  Insert  the  three-way  cannula  into  the  central 
or  cardiac  end  of  the  carotid  artery.  The  cannula  should  have  a 
piece  of  rubber  tubing  on  each  of  the  other  ends.  After  the  cannula 
is  tied  into  the  artery  connect  one  end  of  it  by  means  of  a  rubber 
tube  with  the  manometer.  See  that  it  is  now  filled  with  the  anti- 
coagulant solution,  either  sodium  citrate,  5  to  10  i)er  cent.;  mag- 
nesium sulphate,  6  per  cent,  or  other  solution  as  may  be  provided. 


52  MODES  OF  ADMINISTERING  DRUGS 

See  that  the  system  is  well  filled  and  contains  no  air.  The  other 
free  end  of  the  three-way  cannula  is  connected  in  the  same  way 
with  a  pressure  bottle. 

The  pressure  bottle  may  be  used  as  in  the  illustration  where  the 
pressure  is  transmitted  by  a  hand  pump  to  the  anticoagulant  fluid, 
or  if  the  air  system  of  raising  the  pressure  is  not  used,  the  pressure 
may  be  raised  by  a  pressure  bottle  suspended  at  a  height  of  approxi- 
mately six  to  eight  feet  above  the  operating  table.  If  the  pressure 
bottle  is  used  it  must  be  made  safe  as  it  has  been  known  to  fall  and 
injure  the  operator.  This  last  method  is  used  in  many  cases  where  a 
permanent  working  place  is  provided.  Either  method  is  satis- 
factory. 

Clotting  is  lessened  in  the  three-way  cannula  by  having  a  bulbous 
enlargement  and  the  use  of  an  anticoagulant  solution.  The  enlarge- 
ment of  the  three-way  cannula  permits  mixing  of  the  blood  with 
the  anticoagulant  solution. 

The  pressure  in  all  cases  should  be  raised  to  nearly  that  of  the 
blood-pressure  of  the  animal  before  the  clip  is  released  from  the 
artery,  because  if  the  blood  flows  out  into  the  connecting  tubes  it 
may  clot  and  thus  cause  considerable  annoyance  and  inconvenience, 
and  it  also  takes  the  blood  from  the  vessels  of  the  animal  and  lowers 
the  normal  blood-pressure  to  that  extent.  If  it  can  be  made  to 
balance  within  the  three-way  cannula  this  is  much  more  satisfactory 
from  all  standpoints.  If  too  great  a  pressure  be  placed  on  the  out- 
side, some  of  the  anticoagulant  is  forced  into  the  heart  with  fatal 
effect  in  most  cases. 

Cleaning  Out  the  Cannula. — Place  a  bulldog  clamp  on  the  artery 
again,  and  place  a  pinch-cock  on  the  tube  connecting  with  the  mano- 
meter. Slip  the  tube  off  of  the  cannula  and  swab  the  cannula  with 
a  feather.  Fill  the  cannula  system  with  MgS04  solution  (6  per  cent.), 
sodium  citrate  5  per  cent.,  or  any  other  anticoagulant  solution. 
The  main  points  to  observe  in  washing  out  the  cannula  is  that 
fluid  be  not  injected  into  the  heart,  or  clots  or  air  washed  into  the 
circulation.  If  the  cannula  is  to  be  cleaned  after  it  is  removed  from 
the  body,  it  may  be  soaked  in  5  per  cent.  NaOH  for  some  time. 
This  dissolves  the  blood,  fibrin,  etc. 

RECORDING  RESPIRATION. 

Insert  a  tracheal  cannula  and  connect  it  with  one  horizontal 
limb  of  a  T-tube  by  means  of  a  short  rubber  tube.  The  other  hori- 
zontal limb  of  the  cannula  is  connected  with  the  ether  bottle.    The 


GRAPHIC  RECORDS  ■ 53 

vertical  limb  of  the  T-tiibe  is  connected  with  a  rubber  tube  long 
enough  to  reach  a  tambour  registering  on  a  kymograph  drum. 
(Records  of  .respiration  obtained  in  this  manner  are  comparable 
only  so  long  as  the  openings  into  and  from  the  ether  bottle  are  kept 
constant.  It  is  evident  that  if  these  are  adjusted  during  the  course 
of  the  experiment,  there  is  bound  to  be  an  inaccuracy  in  the  record. 

GRAPHIC  RECORDS. 

In  making  these  records,  the  writing  levers,  tambour,  etc.,  must 
be  so  arranged  that  all  writing  points  are  in  the  same  vertical  line. 
In  most  cases  it  is  a  good  idea  to  have  a  time  record.  If  the  labora- 
tory has  a  "time"  circuit,  this  is  connected  with  a  signal  magnet 
writing  on  the  drum.  If  such  a  circuit  is  not  available,  the  time 
magnet  is  connected  in  series  with  a  dry  cell  and  key.  A  student 
should  be  prepared,  with  a  watch  before  him,  to  make  contacts  at 
stated  times.  Accuracy  in  this  matter  is  assured  by  close  attention 
only.  The  wire  connection  should  be  long  enough  so  that  the  opera- 
tor will  not  be  in  the  way  of  the  experimenting.  Individual  metro- 
nomes are  often  used  to  make  and  break  the  time  circuit;  the  time 
"magnet  may  be  adjusted  in  blood-pressure  experiment's  to  register 
the  zero  pressure.  A  second  signal  magnet  is  arranged  to  write 
directly  under  the  first  to  record  the  instant  and  duration  of  the 
given  procedure.  The  key  controlling  this  magnet  should  be  on 
the  drum  table  conveniently  near  to  the  operator. 

When  the  record  is  completed,  it  should  be  taken  from  the  drum 
and  labeled  at  once  to  prevent  confusions  which  might  arise.  The 
date  and  series,  if  more  than  one  record  is  made  on  one  day,  should 
be  written  on  the  record.  It  is  advisable  to  put  all  data  possible  on 
the  tracing.  Each  experimental  procedure  should  be  legibly  speci- 
fied. The  time  of  each  event  should  be  specified  on  the  record  in 
order  that  calculation  may  be  made  later  of  the  duration  of  the 
experiment  and  the  intervals  between  events.  A  writing  board  or  a 
large  glass  plate  facilitates  the  labeling  of  the  records.  It  should 
have  a  base  large  enough  to  hold  the  record  and  a  ledge  with  a  hand 
rest  at  each  side.  After  the  records  are  labelled,  they  should  be 
.shellacked.  When  a  series  of  records  is  made  and  properly  labelled, 
the\'  aft'(jrd  data  on  the  experiment  to  be  studied  at  leisure.  The 
important  sections  may  be  copied  as  blue  prints  and  given  to 
rncrribers  of  the  class. 

Records  of  blood-pressure  may  be  studied  as  follows:  Careful 
measurement  of  the  distance  of  the  tracings  above  tlie  base  line  at 


54  MODES  OF  ADMINISTERING  DRUGS 

various  points  along  the  course  of  the  curve  should  be  made.  This 
means,  before  the  drug  is  injected,  after  it  is  injected,  and  when  the 
action  becomes  apparent,  and  at  intervals  thereafter  according  to 
the  drug  used.  When  the  curve  is  ordinarily  uniform,  readings 
every  minute  are  often  enough.  The  zero  line  marked  on  the  tracing 
is  always  used  to  determine  the  blood-pressure.  The  distance  above 
the  base  line  should  be  doubled,  as  there  are  two  arms  of  mercury 
in  the  manometer.  The  changes  in  the  heart-rate  are  studied  as 
follows : 

Two  parallel  lines  are  drawn  perpendicular  to  the  base  line  so  as 
to  intersect  the  tracings.  The  distance  of  the  lines  from  each  other 
is  determined  by  the  rate  of  the  drum  as  indicated  by  the  time 
marker.  They  are  usually  drawn  to  include  between  them  a  space 
of  ten  seconds,  in  terms  of  the  record.  The  number  of  heart  beats  on 
the  tracing  included  between  the  two  lines  is  counted  and  the  rate 
of  the  heart  per  minute  is  calculated  from  this;  these  estimates  are 
made  along  the  curves  at  the  same  places  where  the  pressure  changes 
are  measured.  Mark  any  other  variation  in  the  curve,  as  irregu- 
larities of  heart  action  or  of  respiration. 


CHAPTER  II. 

EXPERIMENTAL  PHARMACOLOGY. 

Substances  Whose  Main  Action  is  Local.    This  will  include  mainly 
the  pharmacology  of: 
I.  The  skin. 
II.  The  visible  mucous  membranes  of  the: 
Eye. 
Mouth. 
Nose. 
Throat. 
Rectum. 
Vagina. 
Lrethra. 
III.  The  aUmentary  tract. 
In  presenting  pharmacology  in  the  laboratory,  the  logical  sequence 
that  is  followed  in  a  lecture  course,  may  be  very  inconvenient. 
For  this  reason  sequence  is  frequently  sacrificed  to  convenience 
without  detracting  greatly  from  the  value  of  the  work. 

I.  The  Skin. — The  functions  of  the  skin  are  varied  and  complex. 
The  most  important  are: 

1.  It  is  the  protective  covering  of  the  body. 

2.  It  is  the  sensory  surface  which  adjusts  the  body  with  the  outer 
world. 

3.  It  regulates  the  body  temperature,  or  at  least  is  one  of  the 
adjusting  mechanisms. 

4.  It  is  an  excretory  organ. 

5.  In  some  cases  it  is  a  secretory  organ,  (milk  for  example). 
Many  of  these  functions  will  fall  better  under  the  heading  of 

Glands,  Peripheral  Nerves,  Intestines,  etc.  For  that  reason  in  the 
Pharmacology  of  the  Skin  we  will  study  (1)  those  drugs  that  act 
locally  mainly  because  of  their  mechanical  effect;  (2)  those  that  have 
an  action  on  the  skin  due  to  the  excretion  of  drugs  by  the  skin. 

Classification  in  pharmacology  is  for  convenience  only  and  as  an 
aid  to  the  association  of  drug  action.  It  cannot  be  anything  but 
arbitrary  and  overlapping.  Drugs  used  mainly  for  their  action  on 
the  skin  are: 


56  EXPERIMENTAL  PHARMACOLOGY 

1.  Dusting  powders. 

2.  Emollients  and  demulcents. 

3.  Collodions. 

4.  Irritants  and  counterirritants. 

Rubefacients. 

Vesicants. 

Pustulants. 

5.  Antiseptics  and  disinfectants. 

6.  Corrosives  and  caustics. 

7.  Local  anesthetics. 

Drugs  that  act  on  the  skin  either  through  excretion  by  the  skin 
or  through  metabolic  changes  and  includes  especially: 
Iodides. 
Bromides. 
Salicylates. 
Quinin. 
Arsenic. 
Chloral. 
Antypyretics. 
Sulphonal. 
Aspirin. 

8.  Poultices. 

II.  Drugs  used  for  their  action  on  the  visible  mucous  membranes: 

1.  Demulcents  and  emollients. 

2.  Bitters. 

3.  Astringents. 

4.  Corrosives  and  caustics. 

5.  Antiseptics. 

6.  Local  anesthetics. 

These  may  be  used  in  the  form  of  gargles,  lozenges,  suppositories, 
nebulae,  injections,  etc. 

III.  Drugs  used  mainly  for  their  action  on  the  alimentary  tract 
are: — 

1.  Demulcents  and  emollients. 

2.  Astringents. 

3.  Antiseptics  and  disinfectants. 

4.  Carminatives. 

5.  Bitters. 

6.  Digestants. 

7.  Emetics. 

8.  Anti-emetics. 

9.  Acids  and  antacids. 


LOCAL  ACTIOX  OF  DRUGS  57 

10.  Absorbents. 

11.  Drugs  to  lessen  movement  (opiates,  etc.) 

12.  Drugs  to  increase  movements  (cathartics.) 

13.  Anthelmintics. 


LOCAL  ACTION  OF  DRUGS. 

Local  Anesthesia  (an,  not;  aisthetos,  sensible). — Local  anesthesia, 
or  terminal  anesthesia,  may  be  brought  about  by  suppressing  the 
sensitivity  of  the  nerve  ends — terminal  anesthesia,  or  by  blocking 
the  nerve  impulse  in  the  nerve  trunks — nerve  blocking. 

Methods. — Local  anesthesia  may  be  brought  about  by: 

1.  Compression. 

2.  Cold  applications. 

3.  Chemical  agents. 

4.  Local  anemia. 

5.  Infiltration  with  anisotonic  solutions — water,  salt  solutions, 
etc. — which  act  purely  physically. 

6.  Cocain  and  substitutes,  which  may  be  considered  as  a  special 
class  of  chemical  agents. 

The  chief  local  anesthetics  are: 
Ethyl  chloride. 
Ether  spray. 
Extreme  cold. 

Cocain  and  substitutes — prococain  and  tropococain. 
Chloretone. 
Antipyrin. 
Hydrocyanic  acid. 
Creosote,  guaiacol. 
Iodoform. 
Orthoform. 
Phenol. 

Quinin  urea  hydrochloride. 
Local  Anodynes: 
Aconite. 
Veratrin. 
Belladonna. 
Menthol. 
Chloral. 

Sodium  bicarbonate. 
Zinc  oxide. 
Volatile  oils. 


58  EXPERIMENTAL  PHARMACOLOGY 

Experiment  I. — Cutaneous   Sensations. — General  Characteristics. — 

(a)  Pundiform  Distribution  of  Cutaneous  Senses. — Shave  and  mark 
off  an  area  of  skin  on  the  back  of  the  hand  about  one  inch  square. 
Blindfold  the  subject  and  arrange  the  hand  on  a  comfortable 
support.  With  suitable  esthesiometers  explore  the  selected  area 
systematically  for  warm,  cold  and  pressure  spots,  marking  each 
variety  in  a  different  color,  say  red,  blue  and  black  respectively. 
It  will  require  close  attention  to  recognize  the  sensation  aroused  in  a 
touch  spot  and  to  distinguish  it  from  that  of  a  pain  spot,  the  sensa- 
tion lasting  longer  in  the  second  case.  Observe  the  arrangement 
and  relative  numbers  of  the  several  kinds  of  sensory  spots.  Note 
the  variation  in  sensitiveness  within  each  group  and  select  for  later 
experiments  a  few  of  the  more  sensitive  cold  and  warm  spots. 

(b)  Sjiecific  Nerve  Fmergies  (Functions)  of  the  Cutaneous  Nerves. — 
Try  mechanical  or  electrical  stimulation  of  a  cold  spot.  Try  the 
paradoxical  cold  reaction,  i.  e.,  stimulation  of  a  cold  spot  by  applica- 
tion of  a  warm  object  with  a  temperature  of  50°  to  60°  C. 

(c)  Spray  the  area  with  ethyl  chloride  and  repeat  (a)  and  (6). 

(d)  Compress  the  arm  to  a  degree  when  the  circulation  is  markedly 
disturbed  and  repeat  (a)  and  (6). 

Experiment  n.^ — Temperature  Sensations. — (a)  Adequate  Tempera- 
ture of  a  Medium. — This  is  the  temperature  of  the  medium  which 
gives  neither  warm  nor  cold  sensation.  It  is  not  a  definite  tem- 
perature, but  a  temperature  range,  the  extent  of  which  depends 
on  certain  physical  properties  of  the  medium,  such  as  its  specific 
heat,  its  conductivity — for  heat,  the  character  of  its  surface,  etc. 
Compare  oil  and  mercury,  water  and  mucilage  of  acacia,  at  the 
same  temperature.  Practical  method  of  finding  the  temperature 
of  the  skin. 

(6)  Adaptation. — Transfer  the  finger  from  a  bath  of  Hg.  at  the 
adequate  temperature  to  Hg.  a  few  degrees  colder;  the  initial  sensa- 
tion soon  disappears.  Repeat  this  with  colloidal  solutions  at  the 
same  temperature. 

(c)  Contrast. — Find  the  adequate  temperature  of  water  for  the 
fingers  of  both  hands  (approximately  28°  C).  Then  transfer  the 
right  hand  finger  to  water  at  15°  C,  the  left  hand  finger  to  water 
at  40°  C.  After  a  short  interval  return  both  to  the  water  at  the 
adequate  temperature — about  28°  C.     What  sensations  result? 

Experiment  HI. — Pressure  Sensations. — (a)  Observe  the  arrange- 
ment of  the  spots  in  relation  to  hair  follicles  and  demonstrate  the 
influence  of  the  fine  hairs  magnifying  the  effect  of  weak  stimuli. 

(6)  Absolute  Threshold — Liminal  Stimulus.- — This  depends  on  a 
number  of  factors,  such  as  the  qualit}^  of  the  skin,  presence  or 


LOCAL  ACTION  OF  DRUGS 


59 


absence  of  short  hairs,  rate  of  apphcation  of  pressure,  etc.  Find  its 
vahie  for  several  regions,  inchuhng  forehead,  terminal  phalanx  of 
middle  finger  (volar  surface)  and  back  of  hand. 

(c)  Differential  ThresJwld.— Determine  the  differential  threshold 
for  some  one  region,  say  the  skin  of  the  forehead.  The  method  to  be 
followed  may  be  outlined  as  follows: 

The  weights  are  applied  in  succession  to  the  same  area. 

The  interval  between  the  two  applications  should  be  short  (five 
seconds)  and  regular. 

The  duration  of  the  stimulus  must  be  constant. 

There  should  be  no  thermal  element  present  and  visual  and  mus- 
cular sensations  must  be  excluded. 


Fig.  11. — Method  of  pithing  frog. 

(d)  Discriminative  Sensibility  of  the  S/an.— Examine  the  localiz- 
ing power  of  the  same  regions  for  which  the  threshold  stimulus  has 
been  determined,  using  the  older  method  of  Weber,  in  which  no 
regard  is  had  for  the  individual  sense  spots.  Note  that  the  sensi- 
tiveness of  different  regions  for  light  touch  and  for  tactile  dis- 
crimination does  not  vary  in  the  same  manner.  Observe  also  the 
variation  in  the  discriminative  sensibility  of  the  skin  of  the  cheek 
from  ear  toward  the  lii)s,  and  of  the  arm  from  shoulder  to  hand. 


60 


EXPERIMENTAL  PHARMACOLOGY 


Repeat:  (a)  After  the  spots  have  been  anesthetized  with  ethyl 
chloride. 

(b)  After  the  spots  have  been  anesthetized  by  holding  a  piece  of 
ice  to  them. 

Experiment  IV. — Nerve  Blocking. — Pith  a  Frog. — Expose  the 
sciatics;  test  the  response  to  electric  current.  Freeze  a  small 
section  of  the  nerve  with  ethyl  chloride  and  stimulate  above  and 
below  the  frozen  areas. 

Apply  chloroform  and  ether  in  the  same  way.  Results?  What 
can  you  say  of  the  action  of  drugs  on  the  nerve  trunks?  Nerve 
blocking? 


Fig.  12.- 


-Lines  showing  points  to  cut  to  expose  or  remove, 
bellum;  c,  cord  with  sciatic;  d,  sciatic. 


a,  cerebrum;   b,  cere- 


Experiment  V. — Take  a  piece  of  filter  paper  1  cm.  square  and  soak 
it  in  a  1  per  cent,  cocain  solution  and  apply  it  to  your  own  tongue. 
Retain  it  in  position  for  fifteen  seconds,  then  test  the  area  for 
sensations  of  touch,  temperature,  and  taste.  Contrast  the  sensa- 
tion for  quinin,  sugar  and  salt  before  and  after  the  use  of  cocain. 
Cocain  in  medicine  is  used  chiefly  for  its  local  action,  and  this 
mainly  to  abolish  pain. 

Experiment  VI. — Dip  the  foot  of  a  frog  into  a  1  per  cent,  cocain 
solution.  In  a  few  minutes  compare  the  excitability  of  this  foot 
with  the  other,  as  regards  response  to  electrical  stimulation,  mechan- 
ical stimulation  and  chemical  stimulation — dipping  into  1  per  cent. 


LOCAL  ACTION  OF  DRUGS 


61 


HCl  or  acetic  acid.  As  soon  as  the  reflex  is  obtained,  wash  off  the 
excess  of  acid  with  water  in  another  beaker.  (Tiirck  method  of 
reflex  time.) 


Fig.  1.3. — Tiirck  method  of  taking  reflex  or  reaction  time. 

Experiment  VII.— Anesthesia  of  Cornea. — Touch  the  cornea  of  a 
rabbit  with  a  glass  rod  or  other  suitable  instrument  and  note  the 
reaction.  Now  instil  a  few  drops  of  cocain  1  per  cent,  and  from  time 
to  time  determine  the  change  in  reflex  on  stimulation.  Compare 
the  reflex  of  the  cocainized  eye  with  that  of  the  normal  eye.  Note 
also  any  change  in  size  of  pupil.  In  a  second  rabbit  test  the 
ane.sthetic  effect  of  quinin  urea  hydrochloride  in  the  same  way. 

Experiment  VIII.— Place  one  drop  of  the  tincture  of  aconite  on 
your  own  lip  and  note  the  sensations.  A  tingling  scratching  sensa- 
tion is  produced.  The  drugs  of  the  aconite  group  are  the  only  drugs 
whicli  act  on  the  sensory  receptors  when  given  systemically;  i.  c, 
by  mouth,  intravenously,  etc.  Squibbs  test  for  aconite  is  based  on 
this  action.    It  is  as  follows:    Dilute  1  c.c.  of  the  tincture  of  aconite 


62  EXPERIMENTAL  PHARMACOLOGY 

to  70  c.c.  with  water.  Hold  4  c.c.  of  the  diluted  solution  in  the 
anterior  part  of  the  mouth  for  one  minute  and  expel  it.  If  the 
original  tincture  is  of  standard  strength,  a  tingling  sensation  will 
be  distinctly  apparent  in  from  ten  to  fifteen  minutes. 

Experiment  IX. — Compare  Experiment  VIII  with  the  result  from 
an  equal  amount  of  the  tincture  of  veratrin.  These  are  the  only 
drugs  that  give  this  reaction.  How  would  you  distinguish  between 
the  two? 

DEMULCENTS. 

Demulcents  are  colloidal  substances,  chiefly  gums,  dextrins, 
sugars,  starches  or  other  carbohydrate,  which  are  used  mainly  to 
protect  mucous  surfaces,  though  they  may  be  sometimes  used  on 
the  skin.  Their  action  is  purely  mechanical  and  protective.  Bayliss 
has  recently  recommended  the  use  by  injection,  of  6  per  cent,  gum 
acacia  instead  of  physiological  saline  in  cases  of  hemorrhage.  The 
gum  solution  sustains  blood-pressure  better,  and  is,  according  to 
Bayliss,  without  harmful  effects.  (Note:  Give  distinctive  char- 
acteristics of  each  demulcent  mentioned  above.) 

Experiment  I. — Prepare  a  1  per  cent,  cane-sugar  solution  in  water; 
also  a  1  per  cent,  cane-sugar  in  7  per  cent,  mucilage  of  acacia.  Com- 
pare the  taste  of  these.    Explain. 

Experiment  II. — Prepare  in  the  same  way  0.1  per  cent,  saccharin 
(benzosulphonimide)  in  water  and  in  mucilage  of  acacia  or  starch 
paste;  compare  taste.     Explain. 

Experiment  III. — Reduce  a  sample  of  milk  and  of  water  to  a  freez- 
ing temperature  and  compare  the  temperature  effect  on  drinking. 

Experiment  IV. — Prepare  1  per  cent,  acetic  acid  in  water  and  6 
per  cent,  mucilage  of  acacia.     Which  tastes  the  more  acid? 

Experiment  V. — Mix  2  drops  of  the  fluidextract  of  nux  vomica 
with — 

1.  10  c.c.  of  water. 

2.  10  c.c.  of  mucilage  of  acacia. 

3.  10  c.c.  fluid  extract  of  glycyrrhizse.  Compare  the  taste  of  these. 
Experiment  VI. — Add  2  drops  of  a  saturated  solution  of  KI  to 

milk  and  the  same  amount  to  water.  Compare  the  taste  of  each. 
KI  is  best  administered  in  milk.  Is  there  any  other  advantage 
besides  masking  the  taste? 

1.  Explain  the  above  effects. 

2.  What  is  the  philosophy  of  giving  barley  water  instead  of  water 
in  fevers? 

3.  What  are  the  chief  demulcents,  their  preparations  and  doses? 


EMOLLIENTS  63 

Experiment  VII. — (1)  Take  blood-pressure  of  a  dog  by  the  usual 
method.  (2)  Remove  one-fourth  of  the  blood  and  take  record  of 
blood-pressure.  (3)  Inject  the  same  volume  of  physiological  saline 
and  note  effect  on  blood-pressure.  (4)  Repeat  several  times,  noting 
the  time  which  the  blood-pressure  will  hold  up  after  each  saline 
injection.  (5)  After  withdrawal  of  one-quarter  the  blood  volume, 
inject  an  equal  volume  of  6  per  cent,  mucilage  of  acacia.  Compare 
the  effect  of  this  with  the  action  of  physiological  saline. 

EMOLLIENTS. 

Oily  preparations  for  application   chiefly  to  the   skin.     Their 
actions,   like  the  demulcents,  is  purely  mechanical,  and  they  are 
used  to: 
Soothe. 
Protect. 
Soften. 
Relax,  and  as 

Vehicles  for  other  remedies. 
They  are  used  especially  in : 
Abrasions. 
Cuts. 
Bruises. 

Chapped  hands. 
Burns. 

Skin  diseases,  etc. 
They  are  not  often  given  by  mouth  because  of  their  unpleasant 
oily  taste.    They  are  often  used  for  eye,  nose,  urethra,  vagina,  and 
rectum. 
The  principal  emollients  are: 
Adeps. 

Adeps  benzoinatus. 
Unguentum. 
Adeps  lanae  hydrosus. 
Adeps  lanse. 
Petrolates — 

Petrolatum  liquidum. 
Petrolatum. 
Paraffin  durum, 
lilaiid  oils — 
i)[.  olivae. 
01.  gossypii. 


64  EXPERIMENTAL  PHARMACOLOGY 

01.  lini. 

Unguentum  aquse  rosse. 

Cera  flava. 

Glycerin. 

1.  The  petrolates  are  not  absorbed  and  are  used  to  hold  medicines 
to  the  surface  of  the  skin. 

2.  Adeps  penetrates  somewhat  but  not  so  much  as 

3.  Adeps  lanse,  which  is  given  to  carry  drugs  through  the  skin. 
It  is  doubtful  if  these  statements  hold  in  detail. 

Experiment  I. — The  class  will  be  divided  into  groups. 

Group  1.  Take  1  c.c.  ol.  betulse  or  oil  of  wintergreen  by  mouth. 

Group  2.  Rub  2  c.c.  oil  of  wintergreen  or  ol.  betulse  on  the  arm 
or  other  area  of  the  skin. 

Group  3.  Mix  2  c.c.  ol.  betulse  or  wintergreen  thoroughly  with 
10  grams  of  petrolatum  and  rub  on  the  arm  as  in  2. 

Group  4.  Mix  2  c.c.  of  the  oil  with  adeps — 10  grams — and  repeat 
as  in  2. 

Group  5.  Mix  2  c.c.  with  adeps  lanse  hydrosus  and  repeat  2. 

Test  the  urine  every  fifteen  minutes  as  follows:  Acidify  with 
H2SO4.  Add  an  equal  volume  of  ether.  Shake  in  a  separatory 
funnel;  remove  the  ether;  add  water  to  the  ether  extract,  shake  and 
add  a  few  drops  of  Fe2Cl6.  A  violet  color  indicates  salicylic  acid; 
explain  the  reaction.    Make  a  summary  of  results  and  compare. 

DUSTING  POWDERS. 

These  are  protective  and  absorbent. 
They  protect  from — 

Air. 

Clothes. 

Pressure. 

Friction,  etc. 
Any  inert  powder  will  answer  as  a  dusting  powder.     The  main 
preparations  are: 

Talcum  purificatum — magnesium  silicate. 

Kaolinum — aluminum  silicate. 

Fullers'  earth — aluminum  silicate. 

Terra  silicea  purificata — Si02. 

Lycopodium. 

Starch. 

Zinc  oxide. 

Boric  acid.  . 


LOCAL  IRRITANTS  65 

The  essentials  of  a  good  dusting  powder  are:  non-irritant,  impal- 
pable, insoluble  and  light.  They  may  be  mixed  in  any  quantities, 
but  heavy  powders,  like  zinc  oxide,  should  not  constitute  more  than 
20  per  cent,  of  the  weight.  Examine  all  of  the  above  and  make  a 
list  of  the  best-known  dusting-powder  preparations. 

Dusting  powders  are  an  important  class  of  remedies  and  afford 
immense  relief  m  cases  of  irritation  from  clothing,  etc.  Their 
simplicity,  extensive  use  and  freedom  from  the  mysterious,  to  a  great 
extent,  prevents  the  study  they  deserve. 

Experiment  I. — Study  examples  of  each  of  the  above  powders. 

LOCAL  IRRITANTS. 

(Latin — Irrito — Excite.) 

These  if  allowed  to  act  long  enough  produce  the  phenomena  ot 
inflammation,  i.  e.,  redness,  swelling,  pain  and  functional  change. 
What  is  the  difference  between  irritation  and  stimulation? 

Irritants  are  classified  as: 

1.  Rubefacients. 

2.  Vesicants. 

3.  Pustulants. 

This  classification  depends  on  the  degree  of  action,  rather  than 
the  drug  itself.    The  following  are  the  main  representatives: 

Rubefacients.  Vesicants. 

Mustard.  Cantharides. 

Capsicum.  lodin. 

Camphor.  Ammonia. 

Ammonia.  Mustard  oil. 

Arnica.  Boiling  water. 

Alcohol.  Glacial  acetic  acid. 

Ether. 

Chloroform.  Pustulants. 

lodin. 

Oil  of  turpentine.  Croton  oil. 

^'olatile  oils.  Tartar  emetic. 

Friction.  Silver  nitrate. 

Hot  water,  etc. 

Experiment  I. —  Heat. — Touch  the  end  of  a  hot  wire  to  the  skin. 
Treatment,  apply  linimentum  calcis;  explain  the  action.    The  sub- 
ject of  burns  is  pharmac-ological  only  as  the  treatment  involves 
pharmacology.     Most  of  the  treatment,  after  the  removal  of  the 
5 


66  EXPERIMENTAL  PHARMACOLOGY 

caustic  agent  when  this  is  possible,  consists  at  first  in  relieving  the 
pain.  When  this  is  severe,  morphin  may  be  injected.  "  In  many 
cases  the  relief  from  pain  is  affected  by  excluding  external  irritants, 
such  as  air,  etc.  For  this  purpose  carron  oil  was  first  used,  but  has 
now  been  supplanted  by  many  modern  forms  of  treatment,  which, 
however,  follow  out  the  same  principles.  Carron  oil  should  be 
sterile  and  care  should  be  taken  not  to  infect  the  burned  surface. 
A  coating  of  paraffin,  which  melts  at  a  slightly  higher  temperature 
than  that  of  the  body,  forms  a  "skin,"  which  is  said  to  promote 
healing  and  to  prevent  scar  formation.  Many  other  methods  of 
treating  burns  are  advocated.  A  saturated  solution  of  picric  acid 
applied  on  strips  of  sterilized  gauze  has  been  strongly  recommended 
(Power).  The  tincture  of  iodin  (Reclus),  thymol  iodide,  1  to  8  in 
vaselin,  iodoform,  has  been  recommended  in  the  same  way.  A 
solution  of  sodium  bicarbonate  or  carbonate  gives  relief  in  many 
cases  and  is  said  to  promote  healing.  A  saturated  solution  of  boric 
acid  has  also  been  advocated.  Normal  saline  applied  on  cotton  has 
also  been  recommended.  Dusting-powders  of  different  kinds  also 
have  been  used:  acetanilid,  ichthyol,  resorcinol — anything  to  pro- 
tect from  the  air,  and  at  the  same  time  act  as  anodynes.  Immersion 
in  water,  etc.  Paraffin,  which  melts  at  a  temperature  slightly  higher 
than  the  body  temperature,  has  at  present  a  great  vogue.  It  is 
protective,  pliable  and  easily  removable,  because  the  dermis  does 
not  grow  into  it.  It  is  somewhat  painful  to  apply,  because  of  the 
heat  necessary  to  liquefy  it;  but  this  pain  is  greatly  lessened  by 
first  applying  liquid  paraffin. 

Experiment  II. — Apply  a  drop  of  sulphuric  acid  to  the  skin.  When 
it  begins  to  sting,  apply  a  drop  of  sodium  carbonate  or  bicarbonate. 

General  Treatment  of  Burns  and  Scalds. — 1.  Remove  the  corrosive 
agent. 

2.  Neutralize  the  caustic  agent. 

3.  Linimentum  calcis,  liquid  petrolatum  or  other  emollient,  to 
exclude  air  or  irritants. 

4.  Special  treatment. 

5.  Symptomatic  treatment. 

Experiment  III. — ^Apply  5  per  cent,  phenol  to  the  skin  until  it  is 
white.  Immediately  transfer  to  alcohol  or  glycerin.  Explain  the 
whitening  and  the  antidotal  effect.  Phenol  is  much  more  soluble 
in  alcohol  and  glycerin  than  it  is  in  protoplasm.  It  is  not  advisable 
to  dip  the  finger  into  phenol.  If  by  any  chance  the  antidote  is  not 
effective,  the  removal  of  the  skin  from  the  entire  circumference  of 
the  finger  or  limb,  no  matter  how  small,  may  be  a  serious  affair. 


LOCAL  IRRITANTS 


67 


Experiment  IV. — Anesthetize  a  dog  and  introduce  50  c.c.  of  phenol 
or  HgCl;  or  other  corrosive  into  the  stomach  (Fig.  1  and  14).  When 
the  animal  dies  or  is  killed,  make  a  complete  postmortem.  How  would 
you  treat  a  case  of  poisoning  by  phenol  or  corrosive  sublimate? 
Any  corrosivfe?  It  may  be  best  to  leave  this  experiment  until  the 
end  of  some  experiment  in  which  a  dog  is  used,  and  as  a  final  experi- 
ment administer  one  of  these  poisons. 


Fig.   14. — The    cone   method   of   anesthetizing   a   dog.      The   amount  of  ether  and 
air  may  be  regulated  by  the  screw  clamp  and  the  glass  tube  in  the  ether  bottle 


Experiments  V. — Irritant  Emetics. — With  the  exception  of  apo- 
morphin,  all  the  commonly  used  emetics  act  chiefly  by  peripheral 
irritation.  Give  a  dog  50  c.c.  1  per  cent.  CUSO4  by  a  stomach  tube. 
(See  Fig.  7.)  ZnS04,  ipecac,  mustard,  etc.,  act  similarly.  (See 
p]metics.) 

Experiments  VI. — Irritants  may  be  compared  by  placing  them 
on  a  limited  area  of  the  skin  and  covering  them  with  a  capsule, 
beaker,  etc.,  or  with  adhesi\'e  plaster.  Cut  several  pieces  of  adhesive 
plaster  about  one  inch  square.  Place  a  drop  or  its  equivalent  of  the 
following  rubefacients  on  it  and  apply  to  the  skin: 

1.  Croton  oil. 

2.  Ceratum  cantharides. 

3.  Oil  of  turpentine. 

4.  Ammonia. 

5.  Mustard  plaster. 

6.  Oleoresin  of  capsicum. 

Kee[)  these  in  place  for  from  thirty  minutes  to  two  hours  and 
compare  the  intensity  of  the  action.  Do  not  let  them  remain  long 
enough  to  blister.  If  this  happens,  see  treatment  of  burns  and 
sr-alds. 

Experiments  VII. — Remote  action  of  rubefacients.  Take  the 
respiration,  pulse-rate  and  blood-pressure  of  a  student  while  in  a 


68  EXPERIMENTAL  PHARMACOLOGY 

horizontal  position.  Remain  in  the  position  and  apply  a  turpentine 
stupe  to  the  abdomen.  What  is  the  effect  on  the  heart,  respiration, 
etc.? 

This  may  be  repeated  on  different  students  with  chloroform, 
ammonia,  liniment,  mustard  plaster,  etc.  Keep  a  record  of  the  time 
elapsing  between  the  application  and  the  result. 

Experiment  VIII. — Count  the  heart-rate  and  respiration  in  a 
rabbit.  Let  it  inhale  ammonia,  ether,  etc.,  and  record  the  action 
on  the  heart  and  respiration.  Explain  the  nervous  pathways 
involved  in  the  effect. 

Experiment  IX. — Paint  some  tincture  of  iodin  on  the  skin  and 
compare  the  sensation  with  the  effect  when  it  is  applied  on  the 
mucous  membrane  inside  the  lip. 

Experiment  X. — Place  a  drop  or  two  of  chloroform  on  the  back  of 
the  hand.  On  the  other  place  the  same  amount  and  cover  it  with 
a  crucible  or  small  beaker.  What  is  the  difference  in  the  sensation? 
What  harmful  effects  may  result  from  covering  an  area  tightly  to 
which  chloroform  liniment  or  ammonia  has  been  applied. 

Skin  Irritants  and  Rubefacients. — Experiment  XL — Mix  a  table- 
spoonful  of  mustard  flour  and  four  times  its  volume  of  wheat  flour 
with  a  little  water  at  40°  C.  Spread  this  on  a  piece  of  cloth  and 
place  a  piece  of  muslin  over  the  mixture  on  the  cloth.  Apply  to  the 
skin  over  the  stomach  and  cover  with  a  cloth.  Study  the  sensa- 
tion until  the  irritation  becomes  marked.  Take  the  pulse  and 
respiration-rate  before  and  after  the  application.  This  is  often  used 
as  a  domestic  remedy  in  cases  of  colic,  etc.  It  is  valuable  as  a 
remedial  agent  when  properly  used,  but  often  causes  burns  which 
become  infected  and  for  this  reason  must  be  used  with  great  care. 

Experiment  XII. — ^Apply  one  drop  of  chloroform  to  the  arm  and 
cover  with  a  watch-glass  or  with  the  mouth  of  a  bottle.  Linimentum 
chloroformi  is  used  as  a  rubefacient. 

Experiment  XIII. — ^Apply  emplastrum  cantharidis  2"  x  2"  to 
the  skin  as  in  Experiment  II. 

Experiment  XIV. — Snuff  1  grain  of  a  mixture  of  saponin,  in  starch, 
1000.    Do  not  take  more  than  1  grain  of  the  mixture. 

Experiment  XV. — Give  a  cat  1  c.c.  per  kilo  of  saponin,  1  to  1000,  by 
means  of  a  stomach  tube.  Observe  and  record  the  results  for  an 
hour.     Discuss  the  results  obtained. 

Steps  in  the  Actions  of  Irritants. — First:  Tissue  Injury  to  Some 
Degree. — It  may  be  slight  or  severe. 

Second:  Reaction  of  the  Body  to  the  Injury: 

1.  Capillaries  and  small  vessels  dilate,  causing  redness. 


CAUSTICS  OR  ESCHAROTICS  69 

2.  The  vessels  lose  their  tone  and  a  filtration  of  serum  into  the 
region  produces  edema  and  swelHng. 

3.  The  tension  of  the  edema  and  swelUng,  pressing  on  the  nerves, 
causes  pain.    The  nerves  are  also  sensitized  by  toxins. 

4.  Leukocytes  in  the  region  may  disintegrate,  forming  pus. 

5.  Each  of  the  foregoing  operates  to  cause  change  in  function — 
emesis,  lameness,  etc.,  depending  on  the  location  of  the  injury. 

6.  If  the  disintegration  of  tissue  is  great  enough,  the  products 
derange  the  heat  regulating  centers,  and  an  increased  temperature 
results. 

7.  If  the  disintegration  of  tissue  be  considerable,  scars  and  cica- 
trices may  result  and  any  complication  between  restoration  and 
exitus. 

CAUSTICS  OR  ESCHAROTICS. 

These  are  drugs  which  destroy  the  tissues  to  which  they  are 
applied.    They  are  used: 

1.  To  disinfect  wounds,  bites  of  animals,  etc. — phenol,  potassium 
permanganate,  hydrogen  peroxide,  tincture  of  iodin,  etc. 

2.  To  remove  warts,  polypi,  etc.,  HNO3,  H2SO4,  trichloracetic 
acid,  AgNOs  chromic  acid,  etc. 

3.  To  remove  hair-depilatories;  sometimes  used  also  in  tumors, 
neuralgias,  etc.  The  action  is  chemical  or  physicochemical."  They 
precipitate,  dissolve,  or  hydrolyze  the  proteins  of  the  tissues. 

Experiment  I. — To  a  solution  of  the  white  of  an  egg  in  water,  add 
in  a  series  of  test-tubes,  drop  by  drop,  AgNOs,  Fe2Cl6,  HgCl2, 
Pb(C2H302)2,CH3.COOH,HCl,H2S04,NaOH,KOH.  Note  the  con- 
dition of  the  precipitate,  whether  granular,  slimy  or  flocculent.  Add 
an  excess  of  the  reagent  and  note  the  results.  Query:  Which  of  the 
above,  acid,  alkali,  or  salt,  would  cause  the  deepest  corrosion? 
Why?  What  influence  would  the  acid  radical  have  on  the  action 
to  a  corrosive  salt?  Why  has  a  slight  burn  with  an  acid  a  shrivelled 
astringent  appearance  and  feeling  while  that  of  an  alkali  has  a  slimy 
feeling? 

Experiment  II. — Subject  small  pieces  of  muscle,  skin,  etc.,  to  the 
action  of  these  corrosives.  Note  the  difference  in  appearances  and 
feeling.  Dip  the  fingers  into  5  per  cent,  acetic  acid,  and  compare 
with  5  per  cent.  NaOH.  What  is  the  antidote  and  treatment  for 
poisoning  by  each  of  the  above?  (jive  the  symptoms  of  each  and 
an  explanation  of  the  cause  of  each  symptom. 

Experiment  III. — Demondration.     Select  three  dogs  and  give: 
1 .   1 00  milligrams  per  kilo  of  mercuric  chloride  by  stomach  tube. 


70  EXPERIMENTAL  PHARMACOLOGY 

2.  100  c.c.  10  per  cent,  nitric  acid. 

3.  100  c.c.  10  per  cent,  caustic  soda  solution. 

Compare  the  symptoms  carefully  and  when  animals  seem  in 
danger,  apply  the  proper  treatment.  At  the  end  of  the  period,  kill 
the  animals  with  chloroform  and  hold  postmortem.  Compare  the 
gastro-intestinal  tracts  of  the  three.  For  the  postmortem  appear- 
ances, other  animals  may  be  used  which  are  anesthetized  throughout 
the  experiment.  Experiments  of  this  kind  may  be  done  at  the  end 
of  other  experiments. 

Symptoms  and  Treatment  of  Caustic  Poisoning. — Action  on  the 
Alimentary  Canal. — The  introduction  of  caustics  into  the  mouth  is 
either  due  to  accident  or  suicidal  intent.  The  symptoms  are: 
Pain,  nausea,  vomiting,  diarrhea,  tenesmus,  etc.,  anxiety,  vertigo, 
delirium,  convulsions  and  collapse.  The  heart  and  respiration  may 
be  stimulated  at  first,  but  soon  become  weakened  and  fade  away. 
The  symptoms  are  the  same  for  almost  all  irritants  or  caustics. 
Variations  are  not  pathognomonic. 

General  Principles  of  Treatment. — 1.  Neutralize  and  remove  the 
caustic  if  possible. 

2.  Dilute,  give  water  or  milk,  or  other  diluent  in  abundance. 
This  is  given  for  two  reasons:  {a)  to  dilute  and  therefore  lessen  the 
corrosive  action,  since  the  caustic  effect  is  proportional  to  the  con- 
centration; (6)  dilution  favors  removal  of  the  poison. 

3.  Wash  out  the  stomach,  using  stomach-tube  if  it  is  thought  the 
corrosive  action  has  not  gone  far  enough  to  make  perforation  of  the 
alimentary  tract  with  the  stomach  tube  a  probability.  The  use  of 
demulcent  preparations  like  diluted  starch  solutions,  milk,  etc., 
are  pleasant  to  the  corroded  surfaces. 

4.  Give  antidotes:  Chemical  or  physiological  as  are  indicated. 

5.  Sustain  patient  by  symptomatic  treatment — heat  if  necessary, 
or  cold  applications  if  desirable.    Special  treatment  as  indicated. 


CHAPTER   III. 

PHARMACOLOGY  OF  THE  G ASTRO-INTESTINAL 
TRACT. 

The  local  action  of  drugs  on  the  intestine: 

(A)  Specific  Irritants  of  the  Gastro-intestinnl  Tract: 

These  may  be  classified  as: 

1.  Stomachics,  or  Bitters. 

2.  Carminatives. 

3.  Emetics. 

4.  Cathartics  or  Purgatives. 
(5)  Gastro-intestinal  Sedatives: 

Obstipants  or  Astringents. 
(C)  Drugs  Acting  on  Intestinal  Flora  and  Fauna: 

1.  Anthelmintics. 

2.  Intestinal  disinfectants.     With  these  general  disinfectants 
may  be  studied. 

BITTERS. 

These  have  nothing  in  common,  except  the  bitter  taste.     As  a 
group,  they  are  characterized  by  their  bitter  or  aromatic  taste. 
Classification: 

1.  Simple. 

2.  Aromatic. 

3.  Astringent. 

4.  Compound. 

1.  Simple  Bitters. — A  bitter  taste  is  all  that  characterizes  these. 
They  contain  practically  no  tannin  nor  volatile  oil.  They  can  there- 
fore be  used  with  iron  preparations  or  salt  solutions.  They  are 
miscible  with  water. 

Action  of  Iron  on   Tannin?     Salts  on  Oilsf 
The  Chief  Simple  Bitters  are: 
Calumba. 
Quassia. 
Taraxacum. 
CJcntiana. 
(Jhirata. 
Xanthox\lnm. 


72  PHARMACOLOGY  OF  GASTRO-INTESTINAL  TRACT 

Weak  preparations  of  nux  vomica,  quinin,  strychnin,  etc.,  may  be 
used  for  the  same  purpose. 

2.  Aromatic  Bitters. — ^These  contain  aromatic  oils  and  bitter 
principles  but  no  tannin.  They  can,  therefore,  be  used  with  Fe 
preparations. 

Their  alcoholic  preparations  cannot  be  mixed  with  water. 
Principal  Aromatic  Bitters: 

Calamus-sweet  flag. 

Aurantii  amarii  cortex. 

Absinthe. 

Humulus. 

3.  Astringent  Bitters. — Tannin  is  the  prominent  ingredient. 
Volatile  oils  may  be  present  in  small  amounts.  The  preparations 
may  he  mixed  with  water.     They  are,  however,  incompatible  with  Fe. 

Principal  Astringent  Bitters: 
Cinchona. 
Serpentaria. 
Cimicifuga. 

4.  Compound  Bitters. — These  are  blends  of  the  other  preparations. 
Blending  improves  them.  In  most  cases,  these  should  be  given  the 
preference.  Whether  or  not  they  may  be  mixed  with  water  depends 
on  the  choice  of  the  mixture. 

Principal  Compound  Bitters: 

1.  Tinctura  gentianse  composita,  U.  S.  P.  This  contains  no 
tannin,  but  the  coloring  matter  darkens  with  iron. 

2.  Tinctura  cinchonae  composita,  U.  S.  P. 

3.  Elixir  gentianse,  N.  F. 
Physiological  action  of  the  Simple  Bitters: 

These  are  classified  under  the  locally  acting  drugs.  They  are 
administered  by  mouth,  and  their  only  action  is  on  the  alimentary 
tract.  However,  some  of  their  action  may  be  psychic.  One  of  the 
principal  reasons  for  their  administration  is  to  increase  the  appetite 
and  digestion.    Digestion,  however,  has  a  large  psychic  element. 

Local  Action. — Mouth. — All  sensory  nerves  connect,  directly  or 
indirectly,  with  all  motor  nerves.  Hence,  smell,  sight,  thought  of 
food,  contact  with  food  or  drugs,  movements  of  jaw  may  cause  a  flow 
of  saliva.  Taste  reflex  may  cause  a  flow  via  gustatory  nerve  to  the 
salivary  center  in  the  medulla,  and  via  the  chorda  and  sympathetic 
to  the  glands. 

Gastric  Secretion. — 1.  Bitters  cause  less  immediate  secretion  on 
an  empty  stomach  than  does  an  equal  volume  of  water. 

2.  Thirty  minutes  later,  however,  secretion  is  greatly  increased. 


BITTERS  73 

This  increase  diminishes  and  ceases  after  two  hours.     Hence,  the 
reason  for  giving  bitters  half  an  hour  before  meals. 

3.  The  peptic  glands  show  histological  evidence  of  activity. 
(Brekai.) 

4.  The  leukocytes  in  the  blood  are  increased  by  bitters  in  the 
stomach.    Leukocytes  very  probably  aid  in  absorption. 

5.  Bitters  increase  the  gastric  secretion  before  a  Pavlov  meal, 
and  this  taste  reflex  may  explain  the  whole  action  of  bitters. 
(Cushny.) 

6.  Gastric  secretion  is  also  influenced  by  events  taking  place  at  a 
distance,  and  by  psychic  events.  In  a  boy,  whose  esophagus  was 
closed  by  drinking  lye,  the  sight  and  smell  of  food  caused  secretion 
of  gastric  juice.    Sham  feeding,  sight,  etc.,  have  a  great  effect. 

Nerves  Involved  in  the  Secretion  of  Gastric  Juice: 

1.  Cutting  the  splanchnics  has  no  effect. 

2.  If  the  Vagus  be  cut  secretion  stops  (atropin). 

3.  After  allowing  time — three  or  four  days — for  the  constrictors 
to  degenerate,  stimulation  of  the  cut  end  of  the  vagus,  gives  secre- 
tion— the  vagus  therefore  is  the  secretory  nerve.  Hormones  or 
chemical  secretogogues  also  play  a  part. 

Therapeutic  Uses  of  the  Simple  Bitters: 

1.  To  increase  the  appetite  and  promote  digestion. 

2.  In  Convalescence. 

3.  In  Dyspeptics. 

4.  In  Neurasthenia. 

5.  Quassia  as  in  infusion  is  given  as  an  enema  in  cases  of  pin 

worms. 

Experiment  I. — Compare  the  taste  of  each  of  the  bitters  mentioned 
above. 

Experiment  II. — Mix  tincture  of  ferric  chloride  with  a  member 
of  each  class  of  bitters. 

Experiment  HI. — In  a  dog  with  a  gastric  fistula,  take  a  tracing 
of  the  stomach  contractions  without  anesthesia,  and  while  the 
tracing  is  being  taken  place  a  few  drops  of  a  bitter  in  the  animal's 
mouth.     See  Fig  15. 

Experiment  IV. — In  a  dog  with  a  Pavlov  fistula,  collect  the  normal 
.secretion  f(;r  thirty  minutes.  Now  give  2  c.c.  of  tincture  of  gentian 
by  mouth  and  again  collect  for  thirty  minutes. 

Experiment  V. — For  three  successive  days,  each  student  should 
tak(;  0  c.c.  of  tinctura  gentianae  composita,  in  a  glass  of  water,  thirty 
miimtes  before  each  meal.  A  record  of  the  general  feeling  and 
appetite  should  be  kept.     The  three  following  days  take  30  c.c. 


74 


PHARMACOLOGY  OF  G ASTRO-INTESTINAL  TRACT 


syrupus  sarsaparillse  compositus  in  the  same  way  and  compare  the 
effect  produced  by  the  bitter  with  that  produced  by  the  syrup. 
If  groups  of  students  are  Kving  together  the  two  series  may  be  run 
simultaneously. 


Fig.  15. — Method  of  recording  stomach  contractions.  A  water  manometer  is 
used.  The  float  is  made  of  a  phenolsulphonephthalein  ampoule  and  the  tube  to  the 
stomach  ends  in  a  soft -rubber  thimble  of  very  light  rubber.  The  side  tube  with 
screw  clamp  permits  a  sUght  amount  of  pressure  to  be  introduced. 


CARMINATIVES. 

These  are  the  agents  which  aid  or  stimulate  the  expulsion  of 
gas  from  the  gastro-intestinal  tract.  They  thus  prevent  flatulency 
or  the  distention  of  the  stomach  or  intestines  with  gas.  The  active 
ingredient  is  usually  a  volatile  oil  or  resinous  principle.  Other 
carminative  bodies  are  ether,  chloroform,  ammonia,  carbon  dioxide, 
etc.    Carminatives  have  the  following  properties: 

1.  Antiseptic  and  anodyne,  e.  g.,  oils  of  eucalyptus,  cloves  and 
cinnamon,  are  used  in  tooth  cavities  in  cases  of  toothache. 

2.  They  are  general  protoplasmic  irritants,  so  that  when  rubbed 
on  the  skin  they  are  rubefacients. 

Volatile  Oils. — Main  actions  of  volatile  oils: 

1.  Mildly  antiseptic — characteristic  of  benzene  derivatives. 

2.  Irritant  and  rubifacient. 
■3.  Carminative  and  anodvne. 


CARMINATIVES  75 

They  are  used  mainly  as : 

1.  Carminatives. 

2.  Flavoring  agents. 

3.  Genito-urinary  antiseptics. 

Experiment  I. — Examine  and  taste  various  specimens.  This  will 
best  be  accomplished  by  saturating  water  with  the  oils  and  then 
by  tasting  the  water.    Use  any  volatile  oil. 

Experiment  n. — Place  a  drop  of  a  fixed  oil  and  a  drop  of  a  volatile 
oil  on  white  sized  paper,  dry  at  40°  C.  and  compare. 

Experiment  in. — Heat  a  drop  of  a  fixed  oil  in  a  test-tube  with 
KHSO4  over  a  free  flame.  (Compare  odor  with  a  volatile  oil 
treated  in  the  same  way.) 

Experiment  IV. — Swallow  a  drop  or  two  of  any  volatile  oil  on 
sugar.    What  is  the  feeling? 

Experiment  V. — Volatile  oils  are  excreted  in  the  urine,  to  which 
they  often  impart  definite  odors.  They  are  also  excreted  by  the 
lungs.  When  drugs  are  taken  by  the  stomach  it  is  difficult  to  tell 
whether  or  not  they  are  excreted  by  the  lungs  because  the  odor  may 
come  up  by  way  of  the  esophagus.  To  show  that  they  may  be 
excreted  by  the  lungs,  anesthetize  a  dog  and  take  blood-pressure 
tracings.  Insert  a  cannula  into  the  trachea  and  inject  1  c.c.  of  any 
volatile  oil  into  the  femoral  vein.  (Note  the  odor  of  the  exhalation 
in  the  tracheal  cannula.)  Connect  the  tracheal  cannula  with  a 
bottle  of  water  and  see  if  enough  oil  is  exhaled  to  impart  an  odor 
to  the  water.    Does  this  eliminate  excretion  through  the  esophagus? 

Experiment  VI. — Large  doses  of  any  volatile  oil  may  cause  con- 
vulsions. Absinthe  acts  decidedly  on  the  nervous  system  after 
the  prolonged  use  of  small  doses.  Stearoptenes  also  act  as  the 
volatile  oils.  Administer  10  c.c.  per  kilo  of  20  per  cent,  camphor 
in  oil,  by  means  of  a  stomach  tube,  to  a  rabbit  or  inject  one-half 
this  amount  intraperitoneally.  Note  the  peculiar  "bucking"  type 
of  the  spasm. 

Experiment  VII. — Each  student  can  test  at  least  two  of  the  follow- 
ing by  rubbing  some  of  the  drug  on  the  forearm:  Oil  of  turpentine, 
oil  of  peppermint,  menthol,  2  per  cent.,  dissolved  in  alcohol,  chloro- 
form, ether,  or  spiritus  ammonise  aromaticus.  Now,  instead  of 
rubbing,  j;lace  a  few  drops  on  the  skin  and  cover  tightly  with  a 
capsule,  crucible  or  other  device  to  exclude  the  air. 

Experiment  VIII. — Anesthetize  a  rabbit,  cat  or  small  dog.  Take 
respiration  and  blood-j^ressure  tracings.  Inject  20  c.c.  i)er  kilo  of 
20  fjer  cent,  camphor  in  oil  into  the  peritoneum.  Keep  the  anes- 
thesia uniform  and  note  the  action  on  the  heart  and  respiration. 


76  PHARMACOLOGY  OF  G ASTRO-INTESTINAL  TRACT 

Experiment  IX. — Compare  the  action  of  camphor  (Experiment 
VIII)  with,  the  following:  Inject  hypodermically  1  c.c.  per  kilo  of 
0.1  per  cent,  solution  of  veratrin.  Repeat  in  twenty  minutes  if 
necessary. 

Experiment  X. — Fill  six  fermentation  tubes  with  5  per  cent, 
dextrose  solution  containing  yeast.  Keep  one  for  a  control  and  to 
the  others  add  1,  2,  3,  5  and  10  drops  of  oil  of  turpentine.  Shake 
and  place  in  an  incubator  at  40°  C.  and  note  changes  every  15 
minutes  for  3  hours. 

Experiment  XI. — Repeat  experiment  X,  using  oil  of  cloves,  10 
per  cent,  thymol  in  alcohol,  chloroform,  oil  of  peppermint,  oil  of 
cinnamon. 

Experiment  XII. — Fill  a  series  of  small  bottles  with  urine.  Keep 
one  as  a  control  and  treat  the  others  with  the  above  volatile  oils 
(1  c.c.  volatile  oil  to  100  c.c.  of  urine).  Set  in  a  warm  place  and 
note  the  odor  twenty-four  and  forty-eight  hours  later. 

Experiment  XIII. — Separate  students  may  take  1  or  2  drops  of  one 
or  more  of  the  following  drugs  on  a  lump  of  sugar :  Oil  of  turpentine, 
oil  of  peppermint,  2  per  cent,  menthol  dissolved  in  alcohol;  ether, 
1  c.c;  chloroform,  |  c.c,  spiritus  ammonise  aromaticus,  2  c.c.  in 
water.  Is  there  any  action  on  heart-rate  or  respiration?  Have 
they  a  carminative  action? 

Experiment  XIV. — Take  0.3  c.c.  eucalyptol,  0.3  gram  menthol, 
30  c.c.  light  liquid  petrolatum  and  mix.  Use  as  a  spray  for  the 
nose.     (Results?) 

Experiment  XV. — Test  the  solubility  of  volatile  oils  in  alcohol, 
ether,  chloroform  and  fixed  oils.  Compare  and  discuss  volatile 
oils  and  fixed  oils  from  the  point  of  view  of: 

1.  Their  chemistry. 

2.  Their  physical  properties. 

3.  Their  economic  uses. 

4.  Their  therapeutic  uses  and 

5.  Their  fate  in  the  body. 

The  following  are  the  main  therapeutic  uses  of  volatile  oils  and 
other  carminatives  arranged  from  Bastedo  {Pharmacology  and 
Therapeutics) . 

1.  As  anticolics  (in  intestinal  and  uterine  cramps):  Anise, 
peppermint,  dill  water,  distilled  liquor,  essence  of  ginger,  spirit  of 
peppermint,  aromatic  spirit  of  ammonia,  and  Hoffmann's  anodyne. 

2.  As  odors  and  flavors:  Anise,  bitter  almond,  caraway,  cinnamon 
coriander,  fennel,  lavender  flowers,  lemon,  nutmeg,  orange  peel, 
peppermint,  spearmint,  rose  and  vanilla. 


EMETICS  77 

3.  As  correctives  of  irritant  cathartics:  Oils  of  anise,  caraway, 
cloves,  coriander,  fennel  and  peppermint. 

4.  For  t^inpanites  (as  in  typhoid  fever,  pneumonia  or  following 
operations):  By  mouth,  oil  of  turpentine  or  asafetida,  in  pill  or 
tincture;  by  rectum,  oil  of  turpentine,  tincture  of  asafetida,  added 
to  a  soapsuds  enema. 

5.  As  anthelmintics:  Oil  of  chenopodium  for  round-  and  hook- 
worms; th\Tnol  for  hookworms. 

6.  As  stimulants  to  mucous  membranes  of  nose  and  throat: 
Eucal\'ptol,  camphor  and  menthol,  about  1  per  cent,  of  each  mixed, 
with  light  liquid  petrolatum,  and  used  as  a  spray. 

7.  As  antiseptics  and  anodynes:  Oil  of  cloves  or  oil  of  cinnamon, 
in  a  decayed  tooth,  a  drop  on  cotton. 

8.  As  counterirritants :  Camphor,  capsicum  and  menthol,  and 
the  oils  of  mustard  and  turpentine. 

9.  As  stimulants  in  chronic  skin  diseases,  such  as  eczema,  psoriasis, 
etc. :    The  oils  of  cade  and  tar  in  the  form  of  an  ointment. 

10.  As  stimulants  to  the  growth  of  hair:    Oil  of  mace. 

11.  As  antirheumatics:  Methyl  salicylate  in  the  form  of  oil  of 
birch  or  wintergreen.    Also  used  externally  as  a  liniment. 

12.  As  antihysterics :  Asafetida,  camphor,  musk,  sumbul  and 
valerian. 

13.  As  anti-asthmatics:  Powdered  cubebs  smoked  in  cigarette 
form. 

14.  As  bronchial  stimulants:  Creosote,  oil  of  turpentine,  tere- 
bene,  sjTup  of  tar. 

15.  As  diuretics:  Spirit  of  juniper;  fluidextract  of  buchu  and 
uva  ursi. 

EMETICS. 

Experiment  I. — Give  a  dog  1  c.c.  per  kilo  of  0.1  per  cent,  solution 
of  apomorphin  hydrochloride  by  stomach  tube.  Repeat  every  ten 
minutes  until  emesis  occurs.  Record  the  amount  and  the  time 
required  to  produce  vomiting. 

Experiment  II. — Give  the  same  amount  as  in  Experiment  I  sub- 
cutanecnisly  and  record  as  in  P^xperiment  I. 

Experiment  III. — Inject  one-half  of  the  amount  into  the  femoral 
vein  without  an  anesthetic;  compare  Experiments  I,  II  and  III  and 
also  the  following. 

Experiment  IV. — Give  a  dog  50  c.c.  1  per  cent.  CuvS04  by  stomach 
tulxj.  X(jtc  that  there  is  little  nausea  or  depression.  CJ.  Experi- 
ments I,  II  and  III. 


78  PHARMACOLOGY  OF  GASTRO-INTESTINAL  TRACT 

Experiment  V. — Using  another  dog  compare  the  effect  of  the  same 
strength  and  amount  of  ZnS04,  50  c.c.  1  per  cent. 

Experiment  VI. — Tartar  emetic;  give  a  dog  in  the  same  way 
5  c.c.  per  kilo  0.1  per  cent,  tartar  emetic.  Compare  nausea  and 
depression  with  that  produced  in  the  preceding  experiments. 

Experiment  VIL- — Ipecac;  give  by  stomach  tube  0.25  c.c.  of  the 
fluidextract  per  kilo-  body  weight  in  50  c.c.  water. 

Experiment  VIII. — Anesthetize  a  dog  with  chloroform  or  ether 
and  give  twice  the  amount  of  apomorphin  as  in  Experiment  I. 
After  fifteen  minutes  remove  the  anesthetic.    Record  results. 

Experiment  IX. — Give  a  dog  a  hypodermic  of  2  c.c.  of  3  per  cent, 
morphin.  Repeat  dose  in  fifteen  minutes.  After  thirty  minutes 
repeat  Experiment  I. 

Experiment  X. — Many  other  substances  cause  vomiting  when 
injected  intravenously  in  the  unanesthetized  dog,  while  they  may 
be  without  effect  on  the  anesthetized  animal.  The  following  will 
cause  vomiting. 

(a)  5  c.c.  of  5  per  cent,  peptone  solution. 

(b)  1  mg.  per  kilo  body  weight  of  digitoxin. 

(c)  100  mg.  per  kilo  of  digitalis. 

According  to  Hatcher,  this  acts  on  the  vomiting  center  because 
it  will  cause  vomiting  in  the  eviscerated  animal. 

What  are  the  proofs  that  apomorphin  acts  direcdy  on  the 
vomiting  center?      (6)   Give  proofs  that  CuS04  acts  peripherally. 

PURGATIVES  OR  CATHARTICS. 

Purgatives  are  drugs  which  cause  or  hasten  evacuation  of  the 
contents  of  the  bowel. 

Classification  of  Cathartics: 

1.  Chemical. 

2.  Therapeutic. 
Chemical: 

Inorganic : 

1.  Salines,  sulphates,  phosphates,  citrates. 

2.  Sulphur. 

3.  Mercurials. 
Organic : 

1.  Purgative  oils,  castor  and  croton. 

2.  Anthracene  derivatives. 

3.  Resinous  anhydride  or  jalap  group. 

4.  Phenolphthalein. 


PURGATIVES  OR  CATHARTICS  79 

5.  Colloid  and  emollient  laxatives. 
Agar-agar. 
Liquid  petroleum. 
Manna. 
Fruits,  etc. 
Study  the  mechanism  of  the  action.     Is  the  site  of  action  on 
the  small  gut,  the  large  gut  or  on  the  entire  tract? 
Therapeutic  Classification : 

1.  Aperients. 

2.  Laxatives. 

3.  Eccoproctics. 

4.  Cathartics. 

5.  Purgatives. 

6.  Cholagogues. 

7.  Hydrogogues. 

8.  Drastics. 

Discuss  the  advantages  and  limitations  of  each  classification; 
also  discuss  the  mechanism  of  the  action,  the  origin  of  the  fluid, 
the  difference  between  colic  and  inflammation  of  the  gut,  and  the 
uses  and  abuses  of  cathartics.  Besides  the  use  of  drugs,  non-phar- 
macal  measures  may  be  used  to  restore  adequate  or  normal  bowel 
movements.  The  cathartics  should  be  used  only  when  necessary, 
since  the  aim  should  be  to  use  drugs  temporarily. 

Non-pharmacal  Measures: 

\.  Habit  formation  of  the  evacuation  of  the  bowel  reflexes  by 
a  regular  time  for  stool,  persistently  carried  out. 

2.  An  immediate  response  to  the  desire  to  defecate  since,  if  this 
is  not  obeyed  constipation  habits  are  forced  on  the  gut. 

3.  Exercise  is  of  the  greatest  value  in  developing  and  sustaining 
the  tone  of  the  muscles  and  nerves  and  keeping  them  in  a  responsive 
condition,  through  better  circulation. 

4.  Massage  of  the  intestines,  either  normal  or  with  the  aid  of  a 
ball  or  roller,  working  in  the  direction  of  the  bowel  movements. 
This,  however,  cannot  replace  exercise  but  may  act  as  an  adjuvant 
to  exercise. 

5.  Diet  properly  selected,  to  give  a  large  residue,  such  as  vege- 
tables, whole  wheat,  oatmeal  and  other  cellulose  containing  foods. 
The  bowel  needs  a  certain  amount  of  "roughage,"  since  it  must 
have  exercise  as  any  other  organ. 

Demonstration  of  the  influence  of  concentration  on  the  action  of 
a  i)urgative. 


80  PHARMACOLOGY  OF  GASTRO-INTESTINAL  TRACT 

Experiment  I. — 1.  Keep  two  dogs  without  food  or  water  for 
twenty-four  hours. 

2.  Then  administer  to  one  3  c.c.  of  35  per  cent,  sodium  sulphate 
per  kilo  body  weight  and  place  in  a  cage  for  observation. 

3.  To  the  other  give  25  c.c.  of  water  per  kilo  of  body  weight. 
After  an  hour  give  3  c.c.  of  35  per  cent,  sodium  sulphate  per  kilo 
and  in  addition  200  c.c.  of  water.  (Compare  the  cathartic  action  of 
the  salt  in  this  dilute  form  with  that  of  Dog  1,  in  which  the 
concentrated  solution  was  used.) 

Experiment  11.^ — Action  of  Cathartics  on  Man.  -Cathartics  are 
perhaps  the  most  important  and  most  used  group  of  drugs.  For 
this  reason  during  the  course  each  student  should  take  one  of  the 
following  cathartics  each  week,  until  all  have  been  taken  and  keep 
record  of  the  color,  consistence,  size  and  number  of  stools,  griping, 
etc.  Valuable  information  regarding  the  action  of  cathartics  can 
be  obtained  in  this  way  that  can  be  obtained  in  no  other  way. 

(a)  Pilulse  aloes,  2  pills. 

(6)  Calomel,  0.06  gram  and  repeat  in  two  hours. 

(c)  Aromatic  fluidextract  cascara  sagrada,  4  c.c. 

(d)  Epsom  salts,  20  gm.  in  a  glass  of  water  followed  at  once  by 
another  glass  of  water  only. 

(e)  Castor  oil,  15  to  25  c.c. 

(/)  Petrolatum  liquidum,  30  c.c. 

(g)  Phenolphthaleinum,  0.2  gm. 

(h)  Resinapadophyllum,  0.01. 

(i)  Syrupus  sennse,  8  c.c. 

(j)  Jalap,  1  gm. 

For  comparison  all  of  these  had  best  be  taken  in  the  evening  or 
at  bedtime. 

Experiment  in. — Moreau  Loop  Experiment. — Use  physiological 
salt  solution  in  the  middle  loop  and  any  of  the  other  cathartic 
solutions  in  the  other  two.    Make  at  least  three  loops  as  follows: 

Anesthetize  a  dog  with  ether.  Expose  the  intestines  by  an  incision 
along  the  linea  alba.  Handle  with  extreme  care  and  keep  them 
warm,  so  that  absorption  is  as  nearly  normal  as  possible.  Isolate 
along  loop  of  the  small  intestine  as  near  the  large  intestine  as  pos- 
sible. Ligate  this  at  the  upper  end  and  carefully  squeeze  the  con- 
tents toward  the  large  gut.  Now  divide  the  emptied  small  intestine 
into  segments  of  exactly  three  or  four  inches  in  length.  Each 
segment  must  be  exactly  the  same  length.  Place  10  c.c.  physio- 
logical saline  in  the  middle  loop.  Do  this  without  injuring  the  gut. 
Place  the  same  amount  of  any  of  the  other  solutions  mentioned 
below  in  the  loops  on  each  side  of  the  saline  loop. 


PLATE   I. 

CATHARTICS. 

These  diagrams  are  intended  to  show  the  different 
ways  in  which  cathartics  may  act. 

It  is  not  possible  to  classify  strictly,  as  the  action  of 
some  is  too  extensive  to  be  limited  to  one  group  or 
illustrated  by  a  single  diagram. 

The  numbers  indicate  the  diagrams  that  represent 
what  is  believed  to  be  the  most  prominent  action  in 
case  of  each  drug,  without  intending  to  show  the  com- 
plete action  in  every  instance. 

Group  A.     LAXATrVT:S. 

Fruits.     (1) 

Sugar. 

Sulphur. 

Purges  in  small  doses. 

Glycerin  (by  enema).      (2) 

Group  B.     PURGES. 

Anthracenes.      (1) 
Aloe.     (1) 

Mercurials.     (4)   (5) 
Oleum  Ricini.      (.3)    (4) 
Rliamnus  Frangula.     (1) 
Cascara  Sagrada.      (1) 
Rheum.     (1) 
Magnesia.      (3) 
Senna.     (1) 


Group  C.     HYDKAGOGUES. 

Salines. 
Magnesii  Citras.     (3) 


Magnesii  Sulphas.      (3) 
Potassii  Bitartras.     (3) 
Potassii  et  Sodii  Tarti-as. 
Sodii  Phosphas.     (3) 
Sodii  Sulphas.      (3) 


(3) 


Elaterinmn.     (4) 
Jalapa.     (4) 
Senna.     (1)   (4) 


Group  D.     DKASTICS. 

Colocynthis.      (5) 

Oleum  Tiglii. 

(5) 

Elaterinum.      (3)    (4)    (5) 

Podophyllum. 

(5) 

Jalapa.      (3)    (4) 

Scammonium. 

(5) 

Cambogia.      (5) 

Resins.      (5) 

The  red  color  shows  the  site  of  action,  and  indicates 
stimulation  of  motility  or  secretion. 


3.  Secretion  stimulated. 


PLATE    I. 


CATHAKTICS. 

The  natural  provision  for  intestinal  evanmtion  in- 
cludes three  factors: 

Fin<f.  A  certain  amount  of  iiuligestilile  matter  in 
the  foiKl. 

Second.  Peristaltic  motion  from  tlie  stomach  down- 
ward. 

Third.     A  certain  degree  of  fluidity  of  contents. 

A  decrease  of  any  one  factor  tends  to  constipation, 
while  an  increase  tends  to  diarrhoea. 

Cathartics  act  by  influencing  these  several  factors. 

Laxative  foods  act  by  reason  of  their  indigestible 
residue.  Almost  any  cathartic  may  have  simjjly  a 
laxative  effect  when  used  in  small  doses. 

Purgex,  by  their  irritating  action,  stimulate  peris- 
talsis, the  milder  ones  acting  mainly  upon  the  large 
intestine  (1).  Some,  in  large  doses,  approach  drastics 
in  severity  of  action  (5).  The  absence  of  bile  dimin- 
ishes the  activity  of  podophyllum,  jalapa,  rheum, 
senna,  and  scammonium. 

ITydrai/o^pifs  act  in  two  ways: 

Tlie  less  irritating  salines  cause  a  marked  increase 
of  fluid  by  determining  a  flow  of  serum  from  the  blood 
into  the  intestine  (o).  A  low  blood-jjressure  diminishes 
their  activity. 

The  more  irritating  liydragogues  stimulate  very 
promptly  ])eristalsis  of  the  small  intestine,  with  tlie 
result  that  the  fluid  contents  are  hurried  onward  and 
absoi-ption  is  lessened  (4).  Secretion  also  may  be  in- 
creased.     Copious  liquid  stools  result. 

Draxtlrs  stimulate  jiowerfidly  the  ]>eris)altic  move- 
ment of  the  whole  tract  (5),  causing  ])rompt,  frequent 
stools,  with  severe  griping.  Tn  large  dost-s  they  act  as 
irritant  j)oisons,  and  may  cause  contractions  in  the 
gravid  uterus. 

Clioldi/iifjiies  favor  the  flow  of  bile  into  tlie  (hiodemnn, 
probably  through  the  increased  peristalsis.  The  in- 
fluence of  cathartics  upon  the  function  of  thi'  liver 
seems  uncertain  and  indirect. 


Tlie  rod  color  shows  Iho  site  of  action,  ami  indicates 
sliiniilatiou  of  motility  or  secretion. 


OBSTIPANTS  OR  ASTRINGENTS 


81 


(a)  20  per  cent,  magnesium  sulphate. 

(b)  20  per  cent,  sodium  phosphate. 

(c)  10  c.c.  castor  oil  containing  two  drops  of  croton  oil, 

(d)  Fluidextract  of  rhubarb. 

(e)  Fluidextract  of  senna. 

(/)  10  per  cent,  solution  of  phenolphthalein. 
(g)  Liquid  paraffin. 

At  the  end  of  two  hours  carefully  collect  the  fluid  in  the  loops  and 
measure  it. 


Fig.   16.- 


-Moreau  loop    method  of  studying  the  absorption  of    liquids- 
cathartics— from  the  intestine. 


sspecially 


Compare  Results. — If  several  groups  are  doing  this  experiment, 
water,  sugar  solutions,  serum,  etc.,  may  be  added  to  the  list  and  the 
results  of  each  group  tabulated. 

\Vhile  waiting  for  the  two  hours  to  pass,  blood-pressure  experi- 
ments, like  epinephrin,  may  be  carried  out  on  these  animals. 

Experiment  IV. — All  cathartic  salts  precipitate  calcium.  To  a 
solution  of  calcium  chloride,  in  a  series  of  test-tubes,  add  a  few 
drops  of: 

(a)  Magnesium  sulphate. 

(6)  Sodium  phosphate. 

(c)  .Sodium  citrate. 

(d)  Sodium  and  potassium  tartrate. 

Calcium,  therefore,  has  an  anticathartic  or  obstipant  action. 
Attempts  have  been  made  to  find  centrally  acting  cathartics,  but 
so  far  no  practical,  centrally  acting  cathartic  has  been  found. 


OBSTIPANTS  OR  ASTRINGENTS. 

Obstipants  have  the  opposite  action  of  cathartics  and  are  used 
when  the  movements  of  the  bowel  are  too  frequent,  or  are  painful 
6 


82  PHARMACOLOGY  OF  GASTRO-INTESTINAL  TRACT 

because  of  griping.     They  are  in  the  main  locally  acting  drugs. 
They  are  classified  as 

1.  Acids:  Tannic  acid  and  tannin,  tannalbin,  tannigen,  etc. 

2.  Metallic  Salts:  Bismuth  and  cerium  salts,  lead  acetate,  alum, 
silver  nitrate,  ferric  chloride,  etc. 

3.  Bases  or  alkalies:  Calcium  hydroxide. 

4.  Alkaloids:  Atropin,  morphin. 

5.  Inert  Powders:  Charcoal,  talcum,  etc. 

Acids. — Tannin  or  tannic  acid  is  the  astringent  principle  of  all 
plants.     It  acts: 

1.  By  precipitating  proteins  within  the  gut  and  rendering  it  less 
irritable. 

2.  By  direct  action  on  the  gut,  causing  a  constriction  and  possible 
covering  of  the  sensory  nerves  by  a  constriction  of  the  surfaces  over 
them. 

3.  By  forming  a  mechanical  coating  or  precipitate  over  the  sur- 
face. In  all  cases  they  lessen  the  sensitivity  of  the  gut  or  nerves, 
and  leave  the  nerves  less  exposed  to  the  action  of  irritating  products 
in  the  gut. 

The  chief  vegetable  astringents  are: 

Acidum  tannicum:  dose,  |  to  1  gram. 

Tinctura  gambir  composita:  dose,  2  to  4  c.c. 

Tinctura  kino:  dose,  2  to  4  c.c. 

Extractum  krameriee :  dose,  2  to  4  c.c. 
Metallic  Salts. — Bismuth  subnitrate  or  subcarbonate  are  most 
used.  Their  action  is  believed  to  be  chiefly  mechanical,  acting  as  a 
dusting-powder  to  the  intestine  and  so  protecting  it  from  irritation. 
There  may  also  be  some  astringent  and  absorbent  effect.  These 
salts  were  formerly  used  by  roentgenologists  for  the  purpose  of 
photographing  the  gastro-intestinal  tract,  but  they  have  largely 
been  supplanted  by  barium  sulphate. 

Ferrous  sulphate,  tinctura  ferri  chloridi,  have  been  used  to  some 
extent  in  diarrhea.  Alum  has  also  been  used;  also  silver  nitrate. 
All  of  these,  however,  are  slightly  irritating,  and  at  the  present  time 
are  used  more  as  local  styptics. 

Calcium  Hydroxide. — Chiefly  used  in  the  form  of  liquor  calcis, 
which  contains  0.15  per  cent.  Ca(0H)2.  Calcium  acts  as  an 
obstipant  by  neutralizing  the  acid  product  in  the  intestine,  by  lessen- 
ing the  excitability  of  .the  sympathetic  system,  by  a  direct  depress- 
ing effect  on  the  muscle  and  by  lessening  of  the  permeability  of  the 
capillaries.  In  case  of  children,  when  lime  water  is  mixed  with  the 
milk,  clotting  in  the  stomach  is  modified  and  the  clots  are  smaller, 


PLATE   lie 


MORPHINE. 


In  form  of  sulphate,  acetate, 
or  HYDROCHLORIDE.  Gr.  ^-J  (Gm. 
.008-.015). 

Classified  as : 

Anodrne.  Narcotic. 

Physiologic  action  ; 

The  action  of  morphine  is  essen- 
tially that  of  a  central  nerve 
depressant,    the   L^cal    action 
of  the  drug,  wherever  applied, 
being  almost  7iil  except  on 
the  gastro-intestinal  tract.    Children  are  very 
sensitive  to  this  drug,  and,  if  needed,  it  should 
be  vsed  in  the  weakest  preparations,  and  in 
less  than  the  proportioruil  dose. 
Ifenmis  System. 

Brain.     I)ej)resses  cerebrum,    especially   in    its 
higher  intellectual  functions. 

Medulla.      Depresses  respiratory  center. 

Spinal  Cord.     Stimulates  spinal  cord. 


Vagus  Center 

Vaso  Motor 

Center 
'Cervical 
Sympathetta 


Nerves.  The  peripheral  nerves 

are  not   aSected  by  ordinary 

doses. 
Mimcidar  System.     Not  affected  by 

ordinary  doses. 
Cfirculudon.     Not  much  influenced 

by  ordinary  doses. 
Heart.  Opinions  diflfer.  Any  in- 
fluence of  a  moderate  dose  must 

be  slight  and  probably  indirect. 

I.,arge  doses  slow  the  lieart  by 

stimulating  inhibition. 
Capillary  area.     Not  mucli 

influenced,  except  that  tlie  cu- 
taneous area  of  the  Jiead  and 

neck  may  show  dilatation. 
Respiration.     Depressed  to  a  dcgiee  corresj)on<li 

size  of  dose. 
JtAfe.     Pupils  contracted  by  central  nerve  inlluence. 
JHffejflive  Synfem. 

Stomach.      Secretion  iind  motility  lessened. 
Intestines.      Peristalsis  is  greatly  <limiriislic(l. 
JiJliiii  mill  ton.     Secretions  generally  are  diminished,  excej)!  the  perspiration.     The  drug  is 

partly   chang<'d    in    the   system,   but   the  greater  part    is   climiriMtcd    by  the  gastro- 

iotC'Stinal  tract. 


Pelvic  Plexus 


OBSTIPANTS  OR  ASTRINGENTS  83 

and  more  easily  digested.  Its  action  on  intestinal  movement  can 
readily  be  seen  either  by  direct  application  or  by  intravenous 
injection. 

Alkaloids. — The  alkaloids  that  tend  to  cause  obstipation  are  the 
opium  alkaloids — especially  morphin — and  atropin.  Morphin  acts 
on  the  peripheral  nervous  mechanism,  since  Magnus  found  that 
it  exerted  its  constipating  action  after  all  the  nerves  were  cut. 
The  movement  of  the  gut  is  lessened.  Large  doses  in  the  cat  and 
dog  cause  violent  peristalsis  and  diarrhea,  followed  by  a  consti- 
pating effect.    The  increased  peristalsis  never  occurs  in  man. 

Atropin. — Atropin  lessens  the  movements  of  the  gut  in  a  way  not 
yet  understood.  It  was  formerly  taught  that  it  paralyzed  the 
autonomic  (vagus)  endings,  but  Magnus  has  found  that  stimulation 
of  the  vagus  is  still  active  after  atropin.  He  found  that  therapeutic 
doses  lessen  peristalsis,  while  larger  doses  increase  the  movements. 
It  is  probable,  judging  from  the  action  of  atropin  in  other  locations, 
that  the  action  is  a  paralytic  one  on  the  autonomic  endings;  and 
that  the  sympathetic  and  autonomic  fibers  are  not  so  distinct  in 
this  region  as  is  taught  in  most  books. 

Inert  Powders. — Talcum  and  charcoal  or  any  other  inert  powder 
taken  in  larger  doses  may  have  a  constipating  effect,  due  to  absorp- 
tion of  irritant  materials  or  to  the  mechanical  effect  of  coating  the 
gut  over,  as  with  a  dusting-powder. 

Experiment  I. — Add  a  solution  of  10  per  cent,  tannic  acid  to  egg 
white,  milk,  and  peptone  solution. 

Experiment  II. — Hold  10  c.c.  of  the  tannin  solution  in  the  mouth 
for  a  few  minutes.    What  is  the  effect':' 

Experiment  III. — Take  a  strip  or  ring  of  intestine  of  any  animal 
and  attach  to  a  muscle  lever  and  take  tracing  on  a  drum  with  the 
.strip  in  normal  saline.  It  is  not  necessary  that  it  contract.  Now 
replace  the  saline  with  10  per  cent,  tannic  acid  or  tincture  of  kino. 
Note  the  effect  on  the  drum. 

Experiment  IV. — Test  the  action  of  one  or  more  of  the  following 
solutions  by  gargling  the  throat  with  it: 

(a)     Tr.  iodin 1 

Horax 1 

Aq.  camphor 100 

(fe)     Hydrochloric  acid  dilute 4 

Potassium  chlorate 4 

Glycerin .15 

Water  to 250 

(c)  Alum 4 

(jlycerin 8 

Wafer 100 

(d)  Tincture  ferric  chloride 15 

Glycerin 15 

Water 100 


84  PHARMACOLOGY  OF  GASTRO-INTESTINAL  TRACT 

ANTHELMINTICS. 

(Anti,  against;  helminthos,  worm.) 

Anthelmintics  are  drugs  used  to  remove  intestinal  worms.  They 
are  classified  as: 

1.  Vermifuges,  or  drugs  that  expel  the  worm  but  do  not  kill  it. 

2.  Vermicides,  or  drugs  that  kill  the  worm.  The  difi^erence  is 
more  theoretical  than  practical. 

An  ideal  anthelmintic  would  act  on  the  worm  and  not  be  absorbed 
or  injure  the  intestine.  There  are  none  such.  All  anthelmintics 
are  absorbed  to  some  extent  and  poisoning  by  them  is  not  infre- 
quent. Their  use  is  possible  because  they  are  absorbed  slowly.  A 
cathartic  is  given  before  the  administration  to  remove  material 
that  might  protect  the  worm  from  the  drug,  and  a  cathartic  is 
given  after  the  drug  for  two  reasons: 

1.  To  aid  in  expelling  the  worm. 

2.  To  expel  and  prevent  absorption  of  the  drug. 

Oils  are  not  recommended  as  cathartics  in  this  case,  because  they 
dissolve  most  anthelmintics  and  aid  their  absorption.  The  most 
important  anthelmintics  are : 

1.  Thymol  or  oil  of  chenopodium  for  hookworm. 

2.  Oleoresin  aspidii  or  pelletierin  tannate  for  tape-worm. 

3.  Santonin  or  oil  of  chenopodium  for  round-worm. 

If  we  had  an  ideal  anthelmintic  its  action  would  be  the  same  in 
the  intestine  as  the  following  experiments  in  a  test-tube.  The 
difference,  however,  in  the  following  experiments  and  the  action  in 
vivo  is,  that  in  the  test-tube  there  is  no  absorption,  while  in  the 
intestine  absorption  complicates  the  action. 

Experiment  I. — Demonstration;  ascaris  may  be  obtained  from 
pigs  at  the  slaughter  house.  Keep  in  NaCl  and  0.1  per  cent,  sodium 
carbonate.  For  comparison  place  in  beakers  and  keep  at  37°  to 
40°  C. 

1.  Normal. 

2.  Oil  of  chenopodium  to  saturation. 

3.  Thymol  to  saturation. 

4.  Male  fern,  1  per  cent,  mixture. 

Experiment  II. — Tape-worms;  the  intestines  of  dogs  usually  con- 
tain worms  of  this  type.     Repeat  Experiment  I. 

Experiment  III. — Repeat  Experiment  I,  using  ordinary  earth- 
worms.^ 

1  See  Jour.  Am.  Med.  Assn.,  1919,  Ixxii,  1228;  also  Jour.  Phar.  and  Exp.  Therap., 
1918,  xii,  129. 


MOVEMENTS  85 

SECRETIONS     MOVEMENTS— ANTISEPSIS. 

1.  Secretions. 

2.  Movements. 

Absorption. 

Excretion. 

Peristalsis. 

3.  Antisepsis. 

Of  these  the  secretions  have  been  studied. 

MOVEMENTS. 

Absorption. — All  parts  of  the  tract  absorb  to  some  extent,  but 
the  small  intestine  and  rectum  seem  to  absorb  drugs  much  more 
rapidly  than  the  other  parts.  The  stomach  is  practically  not  an 
absorbing  organ.  The  following  is  the  approximate  time  in  which 
a  large  dose  of  strychnin,  0.1  gram,  caused  convulsions  in  a  rabbit 
when  administered  in  the  same  way  in  isolate  loops  or  parts  of  the 
alimentary  tract: 

1.  From  rectum,  convulsions  in  about  two  hours  seven  minutes. 

2.  Small  intestine,  convulsions  in  about  two  hours  ten  minutes. 

3.  Colon,  convulsions  in  about  two  hours  fifteen  minutes. 

4.  From  esophagus,  convulsions  in  about  one  hour. 

5.  From  stomach,  no  convulsions  after  two  hours. 

Most  other  drugs  and  water  are  not  absorbed  from  the  stomach; 
however,  volatile  drugs  like  alcohol  are  absorbed  and  facilitate  the 
absorption  of  those  drugs  that  are  not  absorbed. 

Acceleration  of  Absorption. — Alcohol,  carbon  dioxide,  volatile  oils, 
spices  and  anything  that  will  cause  slight  irritation  of  the  gastric 
intestinal  tract  will  aid  absorption.  If  the  irritation  be  too  great  it 
may  have  the  opposite  efl'ect. 

Retardation  of  Absorption. — There  are  a  certain  number  of  drugs 
that  retard  absorption  and  movement  of  the  intestine.    The  most 
important  are: 
Morphin. 
Atropin. 
Tannins, 
ijismutli  salts. 
Iron  salts. 
Calcium  salts. 

Coljciidal  material  like  gums,  starches,  pectins,  etc. 
Studv  the  mechanism  of  the  action  in  each  case. 


86 


PHARMACOLOGY  OF  GASTRO-INTESTINAL  TRACT 


Excretion  of  Drugs  into  the  Intestine. — Excretion  into  the  intestine 
has  been  mentioned  under  intestinal  secretions.  Just  how  much 
occurs  through  the  glands  and  by  other  channels  is  impossible  to 
state.  Most  drugs  that  enter  the  body  may,  to  some  extent,  be 
excreted  into  the  intestine,  either  as  such  or  as  their  oxidized  or 
conjugated  products.  This  is  especially  true  of  the  heavy  metals, 
alkaloids,  drastic  cathartics,  arsenic,  antimony,  calcium  salts  and 
toxins. 

-=— ^ <£. 


^o- 


A 


Fig.  17. — Trendelenburg  method  of  recording  intestinal  contractions, 
attached  to  intestine;  B,  in  position  to  take  record. 


A,  tube 


Intestinal  Movements. — There  are  three  classes  of  movement  seen 
in  the  intestine: 

1.  Pendulum  movements  due  to  contraction  of  the  longitudinal 
muscles  mainly. 

2.  Peristalsis,  or  an  orderly  forward  progression  of  the  intestinal 
contents,  due  to  contraction  of  the  circular  muscles. 

3.  A  rolling  movement,  described  by  Meltzer,  Cannon  and  others, 
which  consists  of  vigorous  sudden  waves  of  contraction  which  forces 
the  intestinal  contents  forward  through  long  segments  of  the  small 
intestine. 

Mechanism  of  the  Movements. — The  intestinal  movements  are 
automatic  or  myogenic  in  origin  and  not  dependent  upon  the 


INTESTINAL  ANTISEPSIS  87 

nervous  mechanism,  but  the  orderly  control  of  these  depends  on 
the  extrinsic  nerves.  According  to  Meltzer,  the  rolling  movement 
is  due  to  a  simultaneous  augmentation  of  the  vagus  tone  and  a 

weakening  of  the  sympathetic. 

The  I  ncrease  of  Intestinal  Movement— Yanous  agents  may  increase 

intestinal  movements.  ^    . 

1.  Shutting  off  the  circulation  by  causing  partial  asphyxiation. 

2.  Tylechanical  stimulation,  like  pinching  the  gut  wall,  or  increas- 
ing the  intestinal  contents  with  indigestible  food,  liquid  paraffin,  etc. 

3.  Chemical  stimulation. 

(a)  Gases: 

CO2,  CH4,  H2S,  etc. 

(b)  Cathartics: 

Salines. 

Mercurials. 

Phenolphthalein,  etc. 

Oils. 

Anthracenes. 

Colloids. 

(c)  Pituitary  extract. 

Barium  salts. 
Glycerin  suppositories. 
Nicotin. 
Eserin. 
Retardation   of   Movement.— Most   drugs   that   lessen   intestinal 
secretion  will  also  lessen  intestinal  movements.    The  most  important 
are: 

Opium  derivatives. 
Belladonna  derivatives. 
Tannic  acid  compounds. 
Calcium  salts. 
Lead  acetate, 

INTESTINAL  ANTISEPSIS. 

In  many  cases  it  would  seem  to  be  a  distinct  gain  if  the  intestinal 
tract  could  be  disinfected.  All  attempts  at  this,  however,  has  been 
disappointing;  cathartics  generally  by  flushing  out  the  tract  lessen 
putrefaction;  but  it  is  questionable  whether  the  degree  of  change  is 
sufficient  to  have  any  influence  on  the  general  condition  of  the  body. 
Since  infections  generally  are  looked  upon  as  detrimental  because 
of  the  toxemia  they  produce,  it  would  seem  that  in  many  cases 
gastro-intestinal  derangement  might  be  benefited  by  anything  that 
rids  the  body  of  absorbable  toxins. 


CHAPTER  IV. 

ANTISEPTICS  AND  DISINFECTANTS. 

These  are  general  protoplasmic  poisons. 
Classification : 
I.  General  Disinfectants  and  Deodorizers. — ^These  may  be: 

1.  Solids — for  sinks,  cesspools,  water-closets,  etc. 

Copperas. 
Ferrous  sulphate. 
Naphthalin. 
Lime. 
Chlorinated  lime. 

2.  Liquids — for  utensils  of  the  sick  room: 

HgCl2. 
ZnCls. 
Phenol. 
Formaldehyde. 

3.  Gases — for  disinfecting  rooms  and  contents: 
Formaldehyde. 

Sulphur  dioxide. 
Chlorin, 
Cresols  in  smoke. 

II.  Disinfectants  for  Surgical  Supplies: 

1.  Heat,  moist  and  dry. 

2.  Phenol,  5  per  cent. 

3.  Alcohol,  70  per  cent. 

4.  Formaldehyde. 

5.  Mercuric  chloride. 

The  use  of  these  agents  should  be  demonstrated  and  the  advan- 
tages and  disadvantages  of  each  considered. 

III.  Genito-urinary  Disinfectants: 

1.  Hexamethylenamin. 

2.  Salicylates. 

3.  Benzoates. 

4.  Copaiba. 

5.  Oil  of  sandalwood. 

6.  Salol. 

7.  Creosote. 

8.  Boric  acid. 


ANTISEPTICS  AND  DISINFECTANTS  89 

Experiment  I. — Different  members  of  the  class  will  collect  a  sample 
of  urine  for  control,  then  take  the  average  dose  of  the  following 
drugs  and  repeat  collection  of  urine  every  three  hours: 

1.  Hexamethylenamin,  0.5  gm. 

2.  Sodium  salicylate,  1.0  gm. 

3.  Sodium  benzoate,  1.0  gm. 

4.  Copaiba,  1.0  c.c. 

5.  Oil  of  sandalwood,  0.5  c.c. 

6.  Salol,  1.0  c.c. 

7.  Creosote,  0.25  c.c. 

8.  Boric  acid,  0.5  c.c. 

9.  Methylene  blue  (methylthionse  chloridium),  0.15  c.c. 
Collect  the  urine  in  three,  six  and  nine  hours  after  the  first  dose; 

divide  into  three  samples.  One,  leave  as  excreted;  two,  make 
slightly  alkaline,  and  three,  make  slightly  acid.  Set  all  samples  in 
an  incubator  or  at  room  temperature  and  give  estimate  of  the  rela- 
tive antiseptic  value  of  each  of  the  above.  A  sample  of  normal 
urine  should  be  used  as  a  control  with  each  series. 

IV.  Intestinal  Antiseptics. — In  actual  practice  none  of  these  are 
very  efficient.    They  may  lessen  somewhat  intestinal  putrefaction. 

Place  10  to  15  gm.  of  a  very  finely  divided  meat  preparation 
mixed  with  ground  pancreas,  in  large  test-tubes;  add  the  same 
amount  (0.1  or  0.2  gm.)  of  each  of  the  following  drugs.  Incubate 
at  40°  C.  Observe  two  or  three  times  a  day  and  estimate  the 
relative  efficiency  from  the  odor: 

1.  Control. 

2.  HCl. 

3.  Calomel. 

4.  Charcoal. 

5.  Creosote  carbonate. 
G.  Guaiacol. 

7.  Salol. 

8.  Tannin. 

9.  Thymol. 

10.  Bismuth  subnitrate. 

11.  Glutol  (gelatin  formalin). 

12.  Ilexamethylenamine. 

13.  Sodium  salicylate. 

14.  Sodium  benzoate. 

15.  B.  Xapthol. 

\'.  Antiseptic  IJvsting  Powders. — Place  15  c.c.  of  fresh  defibrinated 
blood  in  a  series  of  test-tubes:  add  to  each  of  the  series  about  10 


90  ANTISEPTICS  AND  DISINFECTANTS 

gm.  of  the  following  drugs.    Close  the  tubes  and  incubate,  observing 
every  day.    Notice  the  color: 

1.  Control. 

2.  Acetanilide. 

3.  Charcoal. 

4.  Kaolin. 

5.  Iodoform. 

6.  Glutol.  . 

7.  Talcum. 

8.  Bismuth  subnitrate. 

9.  Zinc  oxide. 

10.  Tannin. 

11.  Thymol  diiodid  (aristol). 

12.  Calcium  carbonate. 

13.  Boric  acid. 

14.  Betanaphthol. 

Make  a  table  of  the  results,  putting  the  drugs  in  the  order  of  their 
potency,  dividing  them  into  those  which  prevent  putrefaction  com- 
pletely, almost  entirely,  those  which  delay,  and  those  which  have 
no  action. 

VI.  Drying  or  Absorbent  Powders. — ^Powders  are  frequently  used 
as  excipients  when  liquids  are  given  in  capsules,  and  it  is  necessary 
in  such  cases  to  select  one  that  will  absorb  liquid.  They  are  also 
used  to  absorb  gases. 

Mix  1  c.c.  of  defibrinated  blood  with  1  gm.  of  the  powders  men- 
tioned in  Experiment  V  in  small  dishes  and  observe  and  compare 
their  consistence. 

VII.  Antiseptic  Action  of  Alcohol. — Mix  a  cake  of  yeast  with  100 
c.c.  of  water.  Add  10  gm.  of  dextrose  and  shake  thoroughly.  Com- 
pare the  antiseptic  action  of  alcohol  at  different  strengths  as  follows. 
Fill  a  series  of  fermentation  tubes  as  follows  and  place  them  in  an 
incubator  at  40°  C.  or  at  room  temperature: 

1 .  Equal  parts  of  yeast,  dextrose  and  water. 

2.  Equal  parts  of  yeast,  dextrose  and  20  per  cent,  alcohol. 

3.  Equal  parts  of  yeast,  dextrose  and  40  per  cent,  alcohol, 

4.  Equal  parts  of  yeast,  dextrose  and  80  per  cent,  alcohol. 

5.  Equal  parts  of  yeast,  dextrose  and  100  per  cent,  alcohol. 

6.  With  yeast,  dextrose  5  per  cent,  in  alcohol  70  per  cent. 

7.  With  yeast,  dextrose  5  per  cent,  in  alcohol  90  per  cent. 

If  facilities  permit,  different  species  of  bacteria  may  be  used 
instead  of  the  yeast. 


CHAPTER  V. 

DRUGS  CHARACTERIZED  BY  THEHl  ACTION  CHIEFLY 
AFTER  ABSORPTION. 

The  action  of  drugs  after  absorption  may  be  exerted  on  one 
system  or  on  a  number  of  systems.  As  a  rule,  more  than  one  system 
is  acted  upon.  For  this  reason  it  is  advisable  to  study  the  chief 
actions  of  the  drug  and  then  systematize  these  actions  according 
to  physiological  or  anatomical  systems.  It  is  also  advisable  to 
reverse  the  method  of  approach  and  to  study  the  action  of  all  drugs 
that  act  on  a  particular  system,  as  the  nervous  system,  heart,  respi- 
ration or  glandular  system.  It  is  not  possible  to  use  the  two  classifi- 
cations satisfactorily  in  the  same  outline,  so  the  work  should  be  coor- 
dinated by  using  both  classifications,  i.  e.,  the  total  actions  of  one  drug 
and  a  comparison  of  all  drugs  that  affect  each  system .  In  the  following 
outlines  We  have  included  most  of  the  work  on  a  simple  drug  under 
the  system  upon  which  the  drug  exerts  its  most  important  action. 
Caffein  is  found  under  drugs  acting  on  the  kidney  and  digitalis 
under  the  pharmacology  of  the  heart.  All  the  actions  of  alcohol 
may  be  studied;  and  the  action  of  alcohol  on  the  nervous  system, 
heart,  kidney,  etc.,  should  be  compared  with  the  action  of  all  other 
drugs  that  act  on  these  particular  systems.  Comparisons  such  as 
the  action  of  aconite,  digitalis,  strychnin  and  epinephrin  on  the 
heart,  or  atropin,  morphin  and  calcium  on  the  intestine  is  both 
profitable  and  interesting. 

DRUGS  ACTING  ON  THE  CEREBRUM. 

I.  The  Alcohol  Group. — The  action  of  the  alcohol  group  of  drugs 
depends  upon  three  chief  points  of  attack. 

1.  The  local  irritant  action — this  is  due  to  general  action  on  the 
protoplasm.  The  antiseptic  action,  vomiting,  gastric  catarrh, 
degeneration  of  parenchymatous  tissue,  etc.,  are  all  due  to  the 
general  protoplasmic  action. 

2.  Food  value — some  of  its  uses  in  medicine  (le])end  upon  the 
fact  that  it  mav  be  used  as  a  food. 


92  DRUGS  CHARACTERIZED  BY  THEIR  ACTION 

3.  The  action  on  the  central  nervous  system — upon  this  depends 
the  changes  in  reflexes,  psychic  changes,  and  anesthesia,  with  a 
consequent  change  in  all  other  organs.  The  euphoria  alcohol 
produces  is  due  to  an  action  on  this  system. 

For  an  insight  into  the  irritant  action  of  alcohol,  study  Irritants, 
p.  65.  Note  carefully  that  much  of  the  discussion  of  irritants  or 
any  other  drugs  are  statements  of  facts,  and  some  physical  or 
chemical  basis  is  often  advanced  as  a  possible  explanation  of  the 
results  which  the  changed  physics  or  chemistry  entail.  No  complete 
explanation  can  be  given  until  we  know  more  of  the  fundamental 
properties  of  living  matter. 

The  irritant  action  of  alcohol  is  due  either  to  its  direct  action,  or 
to  the  action  of  some  of  its  oxidized  products  on  protoplasm.  The 
irritant  action  is  manifested  by  redness,  increased  circulation,  some 
local  swelling  or  edema,  probably  pain,  some  change  in  function, 
manifested  by  vomiting,  nephritis  or  the  like. 

Alcohol  as  a  Food. — Study  and  carefully  differentiate  between 
drugs,  poisons  and  foods.  Foods  are  something  that  will  give 
up  energy  to  the  body,  repair  waste  and  that  will  not  injure 
the  body.  Unless  it  does  all  three  things  it  need  not  be  considered 
as  a  food.  It  may  be  a  valuable  drug  without  doing  any  of  these 
things. 

Outline  for  study  of  drugs  acting  on  the  nervous  system: 

I.  Brain: 
Cerebrum : 
Psychic  (drugs):    stimulating — caffein,    cocain,   atropin, 
strychnin  (?) — and  depressing.      The   alcohol   group: 
nitrous    oxide,     cannabis,    morphin,    hypnotics    and 
depressants. 
Sensory  (drugs) :  stimulating  and  depressing. 
Motor :  stimulating  and  depressing.    In  general  the  same 
drugs  affect  each  system  in  the  same  way. 

By  psychic  functions  we  mean  those  higher  qualities  which  have 
to  do  with  attention,  observation,  judgment,  perception,  reflection, 
logical  sequence  and  the  like — those  qualities  mainly  in  the  field  of 
psychology.  The  dividing  line  between  what  is  called  psychic  and 
what  is  considered  as  sensory  is  essentially  indistinct — a  kind  of  no 
man's  land. 

Sensation,  or  what  belongs  to  the  sensory  part  of  the  nervous 
system,  cannot  be  sharply  defined  from  the  psychic,  and  sensations 
have  not  been  satisfactorily  classified  by  physiologists. 


THE  ALCOHOL  GROUP 


93 


Formerly  sensations  were  divided  into 

1.  Special: 

Sight. 

Hearing. 

Touch. 

Taste. 

Smell. 

2.  Common: 

Touch. 
Pressure. 
Heat. 
Cold. 
A  more  recent  classification  is : 

1.  External  or  exterior  senses: 

Sight. 

Hearing. 

Taste. 

Smell. 

Pressure. 

Temperature. 

2.  Internal  or  interior  sensations: 

Pain. 

Muscle  sense. 

Hunger. 

Thirst. 

Appetite. 

Sexual  sense. 

Fatigue. 

The  sensations  of  the  semicircular  canals. 

The  sensations  from  the  visceral  organs. 
3^o^,,r  -The  motor  areas  of  the  brain  are  located  along  the  ante- 
rior surface  of  the  fissure  of  Rolando.  The  pharmacology  of  the 
motor  areas  mav  be  studied  separately  from  the  motor  nerve  endmgs 
or  the  reflex  functions.  The  influence  of  drugs  on  the  motor  areas 
mav  be  studied  as  follows: 

Experiment  I.-Anesthetize  a  dog  and  insert  a  tracheal  cannula 
for  artificial  respiration.  When  the  motor  areas  have  been  exposed 
place  a  cannula  in  the  carotid  for  blood-pressure  traangs. 

To  expose  the  motor  areas:  Fasten  the  amma  belly  down  on 
the  operating  board.  With  a  median  incision  cut  the  skni  from  the 
eves  to  the  occipital  condyle.  Detach  as  much  of  the  temporal 
muscle  from  the  bone  as  is  necessary  to  expose  the  region  ot  the 


94 


DRUGS  CHARACTERIZED  BY  THEIR  ACTION 


fissure  of  Rolando.  This  is  well  forward,  and  it  is  advisable  to 
expose  forward  to  the  superciliary  ridge.  Feel  the  condyles  of  the 
lower  jaw  and  join  them  with  a  line  over  the  top  of  the  head.  Draw 
another  line  or  thread  between  the  outer  canthi  of  the  eyes.  The 
fissure  of  Rolando  lies  a  little  posterior  to  the  middle  of  the  distance 
between  these  two  lines.  With  a  trephine,  bore  a  hole  a  little  to  one 
side  of  the  longitudinal  sinus,  which  if  injured  will  cause  consider- 
able trouble.  Lay  bare  an  adequate  area  of  the  brain  so  that  the 
various  motor  areas  may  be  stimulated  with  an  electrode.  In 
stimulating  the  motor  areas,  do  not  use  a  current  that  is  highly 
unpleasant  when  applied  to  the  tongue,  keep  the  areas  moist  with 
saline,  0.8  per  cent. 


NECK. 
FORE.  LIMB. 


Fig.  18. — Motor  areas  in  the  dog's  brain. 


Ether  is  depressant  to  the  motor  areas,  consequently  if  the  anes- 
thesia is  too  deep,  no  action  can  be  obtained. 

Experiment  II. — Try  the  influence  of  light  and  deep  anesthesia  on 
the  sensitivity  of  the  motor  areas.  It  is  often  necessary  to  remove 
the  ether  for  some  time  before  the  areas  can  be  located.  Now 
deepen  the  anesthesia  and  repeat.  ■ 

Experiments  III. — Strychnin  intravenously  in  amounts  just  leading 
to  slight  twitching  will  usually  sensitize  the  mechanism  of  the 
motor  areas.  This  sensitization  is  on  the  cord  because  direct  appli- 
cation to  the  motor  areas  will  not  lead  to  such  good  results.  Paint 
the  arbas  with  a  Httle  0.01  per  cent,  strychnin  and  stimulate  before 


^  u 


THE  ALCOHOL  GROUP  95 

and  after.  Keep  the  strychnin  from  spreading  or  being  absorbed. 
When  satisfied  as  to  the  direct  action  of  strychnin  on  the  motor  areas, 
inject  intra\'enously  0.1  c.c.  per  kilo  of  0.01  per  cent,  strychnin, 
and  again  stimuhite  the  motor  areas.  Let  the  anesthetic  be  Hght 
at  this  period.  Repeat  the  strychnin  injection  if  necessary.  When 
the  motor  area  mechanism  is  decidedly  stimulated,  or  when  the 
animal  commences  to  twitch,  push  the  anesthetic  until  twitching 
ceases.  In  this  way  the  action  of  any  drug  may  be  studied  on  the 
motor  areas. 

Cerebellum. — So  little  is  known  about  the  physiology  of  this 
part  of  the  brain  that  there  is  practically  no  pharmacology.  The 
cerebellum  is  concerned  with  the  equilibrium  of  the  body. 

II.  ]\Iedulla:  Study  the  action  of  drugs  on  the  various  centers: 

Respiration. 

Vagus. 

Vasomotor — constriction  and  dilation. 

Salivary. 

Emetic. 

Sweat,  etc. 

III.  Cord:  The  functions  of  the  cord  are  mainly  conduction  and 
reflexes.     Study  and  record  the  action  of  the  various  drugs  on: 

Sensation. 

Motion. 

Reflexes. 

IV.  Peripheral  nerves: 

Sensory  and  motor :  study  the  action  of  drugs  on  the  nerve 
trunk  and  endings;  myoneural  junction. 

Drugs:  Make  a  list  of  those  that  are  stimulating  and 
depressing  to  each  of  the  above  systems. 

V.  Autonomic: 

Sympathetic  system:  this  system  has  been  discussed  sepa- 
rately. Note  that  it  is  mainly  motor.  In  the  develop- 
ment of  it  from  the  central  nervous  system,  only  motor 
nerves  wandered  out.  These  may  be  constrictor  or  dilator 
in  function.  Study  also  the  action  of  drugs  on  the  nerve 
endings. 

VI.  Ganglion  cells  (drugs): 

Depressing  and  stimulating. 
Make  an  Outline  of  all  Drugs  Stimulating  and  ])epressi^(^  the 
Various  Parts  of  the  Cevfral  Nervous  System  and  (rive  Pro(fs  that 
they  Act  in  the  Manner  Indicated.  Because  they  act  on  other  systems 
also,  these  drugs  cannot  well  be  collected  under  one  heading. 


CHAPTER  VI. 

PHARMACOLOGY  OF  THE  CRANIAL  NERVES. 

The  following  outline  of  the  Pharmacology  of  the  cranial  nerves 
is  given  to  indicate  some  things  to  watch  for  in  the  experiments, 
and  as  an  aid  to  association. 

I.  The  First  Nerve:  N.  Olfactorius  (L,  Oleo,  smell;  faeio,  make). 
— Kant  defined  smell  as  taste  at  a  distance.  Taste  and  smell  are 
closely  related.  The  olfactory  is  a  nerve  of  special  sensation  and 
hard  to  investigate  because  its  receptive  surfaces  are  intimately 
associated  with  those  of  the  fifth  nerve — a  nerve  of  common 
sensation.  For  this  reason  true  smells,  or  those  substances  which 
stimulate  the  olfactory  only  are  hard  to  separate  from  pungent 
substances  like  vinegar  which  also  stimulates  the  fifth  nerve. 

For  the  correlation  of  odor  and  structure  we  ace  indebted  mainly 
to  George  Cohn  {Die  Riechstoffe,  1904)  and  Zwaardemaker  (Physiol- 
ogie  des  Geruchs,  1895). 

Zwaardemaker  separates  pure  odors  into  nine  classes  which  have 
been  arranged  by  Howell  ( Text-book  of  Physiology)  as  follows : 

I.  Odores  setherei  or  ethereal  odors,  such  as  are  given  by  the 
fruits,  which  depend  upon  the  presence  of  ethereal  sub- 
stances or  esters. 
11,  Odores  aromatici  or  aromatic  odors,  which  are  typified  by 
camphor  and  citron,  bitter  almond  and  the  resinous 
bodies.    This  class  is  divided  into  five  subgroups. 

III.  Odores  fragrantes,  the  fragrant  or  balsamic  odors,  compris- 

ing the  various  flower  odors  or  perfumes.    The  class  falls 
into  three  subgroups. 

IV.  Odores  ambrosiaci,  the  ambrosial  odors,  typified  by  amber 

and  musk.  This  odor  is  present  in  the  flesh,  blood,  or 
excrement  of  some  animals,  being  referable  in  the  last 
instance  to  the  bile. 
V.  Odores  alliacei  or  garlic  odors,  such  as  are  found  in  the 
onion,  garlic,  sulphur,  selenium  and  tellurium  compounds. 
They  fall  into  three  subgroups. 
VI.  Odores  empyreumatici  or  the  burning  odors,  the  odors 
given  by  roasted  coffee,  baked  bread,  tobacco  smoke, 
etc.  The  odors  of  benzol,  phenol,  and  the  products  of^ 
dry  distillation  of  wood  come  into  this  class. 


CHEMISTRY  AND  PHYSICS  OF  ODORS  97 

MI.  Odores  hircini  or  goat  odors.     The  odor  of  this  animal 
arises  from  the  caproic  and  capryhc  acid  contained  in  the 
sweat;  cheese,  sweat,  spermatic  and  vaginal  secretions 
give  odors  of  similar  quality. 
\lll.  Odores  tetri  or  repulsive  odors,  such  as  are  given  by  many 
of  the  narcotic  plants  and  acanthus. 
IX.  Odores  nauseosi  or  nauseating  or  fetid  odors,  such  as  are 
given  by  feces  and  certain  plants  and  the  products  of 
putrefaction. 
Beaunis' classified  all  substances  which  affect  the  olfactory  mucous 
membranes  into  three  groups,  as  follows: 

1.  Those  which  act  only  on  the  olfactory  nerves: 

(a)  Pure  scents  or  perfumes,  without  pungency. 
(6)  Odors  with  a  certain  pungency,  e.  g.,  menthol. 

2.  Substances  which  act  at  the  same  time  on  olfactory  nerves, 
and  on  nerves  of  common  sensation  (tactile  nerves),  e.  g.,  acetic  acid. 

3.  Substances  which  act  only  on  the  nerves  of  common  sensation 
(tactile  nerves),  e.  g.,  carbon  dioxide. 

Haller  divided  odors  into: 

1.  Ambrosial  or  agreeable. 

2.  Fetid  or  disagreeable. 

3.  Mixed. 

And  in  every-day  life  the  division  is  usually  made  into : 

1.  Pleasant  or  agreeable. 

2.  Disgusting  or  disagreeable. 

Chemistry  and  Physics  of  Odors. — It  was  formerly  believed  that 
in  order  that  a  substance  be  recognized  as  odoriferous,  particles 
must  reach  the  olfactory  nerve  through  the  air.  However,  odor 
may  be  detected  when  substances  are  dissolved  in  saline  or  in  the 
pharmaceutic  waters  and  taken  into  the  nostrils. 

The  concentration  of  the  substances  in  the  liquid  is  of  some 
importance,  since  cumarin,  vanilin,  oil  of  rose,  etc.,  and  other 
substances  have  different  odors  in  strong  and  dilute  solutions. 

Practically,  however,  volatility  is  the  most  essential  condition 
for  production  of  an  odor.  Since  volatility  is  mainly  dependent  on 
molecular  weight,  chemistry  plays  an  important  part.  In  chemical 
compounds  it  has  been  found  that  certain  groups  or  radicles  give 
rise  to  rather  distinctive  odors.  These  groups  are  called  the  osmo- 
phore  groups  (osme — od(;r;  phero — to  bear).  Two  or  more  osmo- 
phore  groups  may  occur  in  the  same  substance.     Investigation  of 

*  Stewart:     Text-book  <>(  l'\iy»i<Ao:iy. 


98  PHARMACOLOGY  OF   THE  CRANIAL  NERVES 

these  groups  has  not  gone  far  enough  to  classify  odoriferous  bodies 
on  their  chemical  groupings.  The  modifying  influence  of  associated 
groups  is  not  yet  understood.  Hydroxyl,  aldehyde,  ketone,  nitrile, 
nitro  and  azoimide  groups  are  all  osmophoric,  but  may  produce 
pleasant  or  unpleasant  odors,  and  prediction  as  to  the  result  is  very 
uncertain. 

However,  certain  facts  are  established: 

1.  Homologous  derivatives  usually  have  a  similar  odor. 

2.  Phenols  have  characteristic  odors. 

3.  The  odor  of  alcohols  is  usually  pleasant. 

4.  Unsaturated  substances,  which  are  usually  chemically  reactive, 
generally  have  powerful  odors.  Triply  linked  compounds  are 
usually  unpleasant. 

5.  If  an  aldehyde  has  a  pleasant  odor,  reduction  alters  the  odor, 
but  does  not  make  it  disagreeable. 

Drugs  that  act  centrally  may  stimulate  or  depress  the  sensation 
of  the  olfa<itory  nerve,  strychnin  and  caffein  stimulate,  chloral 
depresses.  Cocain  applied  to  the  nasal  mucous  membranes  par- 
alyzes the  sensation  of  smell  entirely.  Marked  changes  in  the  nerve 
may  occur  in  disease  and  the  sensation  of  smell  may  be  entirely 
abolished  (anosmia).    Overstimulation  may  also  cause  this. 

Fatigue  of  the  nerve  is  quite  common.  Odors  soon  give  no  sensa- 
tion when  the  stimulation  is  continued,  and  unpleasant  odors  such 
as  coal  gas,  etc.,  by  continued  action  soon  lose  their  effect. 

Experiment. — Select  different  volatile  oils,  phenols,  etc.,  and 
dilute  to  get  a  pleasant  odor.  Let  each  group  of  students  work  with 
one  odor.  After  smelling  set  to  the  side  and  cocainize  the  nose  by 
plugging  it  with  cotton  dipped  in  0.1  per  cent,  cocain  in  1  to  1000 
epinephrin,  after  a  few  minutes  remove  the  cocainized  cotton  plug 
and  determine  whether  or  not,  the  sense  of  smell  has  been  influenced. 

II.  The  Second  Nerve :  N.  Opticus. — The  second  cranial  or  optic 
nerve  is  the  essential  organ  of  vision.  The  layer  of  rods  and  cones 
are  the  receptive  endings  and  transmit  impulses  to  the  ganglion 
cell  layers  through  the  bipolar  cells.  These  bipolar  cells  may  be 
regarded  as  similar  in  mechanism  to  the  spinal  ganglion  cells,  while 
the  retinal  ganglion-cell  layer,  is  a  part  of  the  central  nervous 
system.  Drugs  that  act  on  the  optic  nerve  are  usually  those  that 
act  on  the  central  nervous  system. 

Drugs  Acting  on  the  Optic  Nerve. — Methyl  alcohol,  especially  when 
its  use  is  continued,  but  even  one  dose  may  so  injure  the  nerve  as 
to  cause  permanent  blindness.  Buller  and  Wood  collected  54  cases 
in  the  United  States  and  Canada.    In  the  month  of  December,  1911, 


THE  OPTIC  NERVE 


99 


70  deaths  from  wood  alcohol  in  cheap  spirits  occurred  in  the  munici- 
pal lodging  house  in  Berlin.  Death,  however,  may  occur  without 
the  optic  nerve  being  directly  involved.  Quinin  sometimes  causes 
a  derangement  of  vision,  but  not  so  often  as  it  disturbs  hearing. 
Filix  mas,  santonin,  pellitierin,  nicotin,  alcohol,  carbon  bisulphide, 
napthols,  etc.,  may  also  act  on  the  optic  nerve.  These  actions, 
however,  are  relatively  rare.  Strychnin  and  caffein  sensitize  the 
nerve  while  central  depressants  have  the  opposite  effect. 

For  experiments  see  Autonomic  Drugs  and  the  various  drugs 
mentioned. 


Fig.  19. — Diagram  to  show  nerves  of  eye  and  submaxillary  gland.  1,  cornea;  2, 
sphincter  pupillse;  3,  dilator  pupillge;  4.  ciliary  muscle;  S,  retina;  6,  optic  nerve;  7,  8, 
short  ciliarj'  nerves;  .9,  ciliary  ganglion;  10,  third  cranial  nerve;  11,  long  ciliary  nerve; 
12,  Gasserian  ganglion;  13,  25,  superior  cervical  ganglia;  11^,  middle  cervical  ganglion; 
15,  inferior  cer\acal  ganglion;  16,  motor  nerve;  17 ,  medulla;  18,  cerebellum;  19,  cere- 
brum; 20,  optic  nerve;  21,  seventh  nerve;  22,  ganglion;  23,  chorda  tympani;  2Jt, 
sympathetic  nerve;  27 ,  submaxillary  gland. 


m.  The  Third  Nerve :  N.  Oculomotorius. — The  third  nerve  is  a 
purely  motor  nerve  that  innervates  both  striated  and  non-striated 
muscle.  The  striated  muscles,  internal,  superior  and  inferior  rectus, 
and  the  inferior  oblique.  These  nerves  arise  from  the  principal 
nucleus  of  the  third  nerve  and  go  directly  to  the  muscle.  The  third 
nerve  also  innervates  the  intrinsic  muscles  of  the  eyeball— the 
ciliary  and  the  sphincter  of  the  iris.    The  ])()rtion  innervating  the 


100  PHARMACOLOGY  OF  THE  CRANIAL  NERVES 

sphincter  arises  from  the  Eppinger-Westphal  nucleus,  while  those 
innervating  the  ciliary  muscles  arise  from  the  median  nucleus. 
Both  these  fibers  pass  to  the  ciliary  ganglion  before  going  to  the 
muscles.  They  are  therefore  autonomic  in  structure.  The  pharma- 
cology of  the  third  nerve  is  concerned  entirely  with  the  autonomic 
portions  of  the  nerve  and  is  studied  especially  under  the  eserine, 
pilocarpin  and  atropin  groups  of  drugs. 

rV.  The  Fourth  Nerve:  N.  Trochlearis.— The  fourth  nerve  is  a 
motor  nerve  supplying  the  superior  oblique  muscle  of  the  eyeball. 
The  pharmacology  of  all  motor  nerves  to  striated  muscle  is  essen- 
tially the  same.  Curare  and  quaternary  ammonium  bases  paralyze 
the  endings  while  eserin  stimulates  them.  Any  drug  may  have  an 
action  on  the  fibers  when  applied  directly  to  them,  but  no  drug  has 
an  observable  action  when  given  any  other  way.  The  centers  of 
the  nerve  may  be  stimulated  by  the  general  centrally  acting  stimu- 
lants or  depressed  by  the  central  depressants. 

V.  Fifth  Nerve:  N.  Trigeminus. — This  is  a  mixed  motor  and 
sensory  nerve.  The  motor  fibers  innervate  the  muscles  of  mas- 
tication— striated  muscles.  The  pharmacology  is  concerned  with 
the  sensory  part  which  mediates  sensations  of  pressure,  pain,  and 
temperature  to  the  face,  scalp,  eye,  nose,  portions  of  ear,  mouth 
and  tongue.  It  is  a  mediator  of  common  sensations.  Some  few 
physiologists  think  it  contains  some  nerves  of  special  sensation  that 
are  given  off  through  the  seventh  and  ninth  nerves. 

The  pharmacology  is  in  general  that  of  sensory  nerve  endings. 
Irritation  of  the  fifth  nerve  endings  by  saponin  or  other  irritating 
drugs,  by  dust,  pressure  through  inflammation  of  the  mucous  mem- 
branes, etc.,  causes  sneezing.  A  trace  of  aconite  also,  in  the  nose  will 
cause  sneezing,  coughing,  a  flow  of  mucus  and  may  produce  vomit- 
ing. Cocain  by  depressing  the  endings  prevents  this.  Drugs  that 
act  centrally  may  stimulate  or  depress  the  fifth  nerve  centrafly. 

VI.  Sixth  Nerve:  N.  Abducens. — The  sixth  nerve  is  a  purely 
motor  nerve.  It  innervates  the  external  rectus.  Its  pharmacology 
is  the  same  as  that  of  any  other  motor  nerve. 

VII.  Seventh  Nerve :  N.  Facialis. — This  is  mainly  a  motor  nerve 
but  it  carries  some  sensory  fibers.  The  motor  fibers  go  to  muscles 
and  glands.  The  muscular  fibers  go  to  the  muscles  of  the  face, 
scalp  and  ear.  The  pharmacology  of  these  is  mainly  the  pharma- 
cology of  voluntary  motor  fibers. 

The  glandular  branches  are  much  more  important.  They  are 
carried  to  the  glands  in  the  chorda  tympani.  The  pharmacology 
of  the  chorda  tympani  is  studied  under  the  atropin  and  pilocarpin 


THE  OPTIC  NERVE  101 

group  of  drugs.    Pilocarpin  and  eserin  stimulate  the  nerve  endings, 
while  the  atropin  paralyzes  them. 

Vni.  The  Eighth  Nerve :  N.  Acousticus.— This  is  a  special  nerve 
and  there  is  but  little  pharmacology  known.  Certain  drugs  like 
quinin,  salicylates,  etc.,  often  produce  ringing  in  the  ears,  but 
whether  this  is  due  to  a  direct  action  on  the  nerve  or  due  to  changes 
in  the  circulation  of  the  region  is  not  known.  Strychnin  and  caffein 
increase  the  acuteness  of  hearing  by  a  central  action.  Morphin, 
chloral,  bromides,  etc.,  depress  by  a  similar  mechanism. 

Experiment.    (Optional). — Place  the  ear  to  a  fixed  opening  in  the 
wall  or  instrument  provided  and  determine  accurately  the  distance 
which  each  student  can  hear  the  ticking  of  a  watch.    Now  give, 
0.03  gram  morphin,  or 
1.00  gram  chloral,  or 
1.00  gram  potassium  iodide,  or 

1.50  c.c.  tincture  cannabis,  or  a  dose  of  any  hypnotic,  and 
determine  the  change  in  hearing  after  one  or  two  hours. 
Similarly  with  other  students  the  change  produced  by: 
3V  grain  strychnin, 
2  grains  caffein,  or 
20  c.c.  80  per  cent,  alcohol. 
K.  The  Ninth  Nerve:    N.  Glossopharyngeus.— This  is  a  mixed 
nerve.     It  supplies  motor  nerves  to  the  pharynx  and  base  of  the 
tongue.    The  pharmacology  of  these  is  the  same  as  other  motor 
nerves.  It  also  supplies  secretory  fibers  to  the  parotid  gland,  through 
Jacobson's  nerve.    This  has  the  same  pharmacological  reactions  as 
the  chorda  tympani. 

The  sensory  nerves  supply  the  posterior  third  of  the  tongue,  and 
the  mucous  membrane  of  the  back  of  the  mouth.  These  parts  are 
influenced  in  the  usual  way  by  aconite,  by  cocain,  etc. 

It  also  supplies  taste  nerves  to  the  posterior  third  of  the  tongue 
but  these  reach  it  from  the  fifth  nerve,  while  fibers  of  the  fifth  nerve 
— lingual — supplies  the  tip.  Some  physiologists  believe  that  the 
ninth  nerve  alone  is  the  nerve  of  taste. 

Before  a  .substance  can  stimulate  taste  it  must  be  soluble  in  the 
fluids  of  the  mouth.  Accordingly  as  they  affect  the  taste,  sapid 
substances  have  been  classified  as  follows: 

1.  Sweet. 

2.  Bitter. 

3.  Acid. 

4.  Saline. 

Regarding  the  mechanism  by  which  sapid  substances  stimulate 


102  PHARMACOLOGY  OF  THE  CRANIAL  NERVES 

the  gustatory  nerve  endings  we  know  but  little,  but  the  stimulus 
acts  on  the  end-organs  and  not  on  the  nerve  trunks.  Nerve  trunks 
in  general  are  Dot  stimulated  by  any  pharmacological  agent,  unless 
it  be  applied  directly;  but  a  sensation  of  taste  is  not  developed  by 
direct  application  to  the  nerve  trunk.  Attempts  have  been  made 
to  find  a  chemical  group  responsible  for  taste,  but  little  progress  has 
yet  been  made.  Acids  and  bases  owe  their  characteristic  tastes  to 
the  H  and  alkalies  to  OH  ions. 

Sternberg  ascribes  the  bitter  taste  of  alkaloids  to  their  cyclic 
constitution.  In  the  Mendelejeff  periodic  classification  of  the  ele- 
ments, the  sweet-tasting  elements  boron,  aluminum,  scandium, 
yttrium,  lanthanum  are  found  in  the  third  group,  while  lead  and 
cereum  are  in  the  fourth.  Beryllium  another  sweet- tasting  element 
is  in  the  second,  while  chlorin,  which  often  gives  rise  to  sweet 
compounds,  is  in  the  seventh. 

The  bitter  elements — magnesium,  zinc,  cadmium  and  mercury 
— are  found  in  the  second.  Sulphur  in  the  sixth  group  often  gives 
rise  to  bitter  compounds. 

The  hydroxyl  group  has  often  been  associated  with  a  sweet 
taste.  Sternberg  (Geschmack  and  Geruch)  has  pointed  out  that  in 
organic  compounds,  in  order  to  have  a  sweet  taste,  the  alkyl  groups 
must  not  exceed  the  OH  groups  by  more  than  one  or  their  com- 
bination will  be  bitter.    Thus  rhamnose : 

CH3(CHOH)4CHO 

is  sweet,  but  methyl  rhamnose 

CHs 

(CHOH)^ 
CH 

> 

CH 

I      ? 
OCH3 

is  bitter. 

Again,  the  sweetness  in  an  homologous  series  increases  with  the 

increase  of  hydroxyl  groups,  e.  g.,  glycocol: 

CH2OH 
CH2OH 

is  sweet,  but  not  so  sweet  as  glycerin : 

CH2OH 

CHOH 

CH2OH 
And  glucose: 

CH3 

(CH0H)4 
CHO 


THE  OPTIC  NERVE 


103 


is  still  sweeter.  That  other  factors  than  the  OH  groups  enter  into 
the  production  of  a  sweet  taste  is  shown  by  the  fact  that  lead 
acetate  is  sweet,  yet  contains  no  OH  groups,  and  saccharin 


C6H4< 


SO2 


CO 


>NH 


is  three  hundred  times  sweeter  than  sugar  and  contains  no  OH 
groups.  It  has  been  suggested  that  the  stimulation  of  the  taste  buds 
is  a  physical  process  due  to  intramolecular  vibrations,  but  we  have 
no  way  of  testing  such  a  suggestion. 

Again  in  those  aromatic  bodies  containing  an  OH  group,  the 
position  of  this  in  the  ring  and  the  relation  to  other  groups  is 
interesting,  e.  g.: 


OH 

/\ 
/        \0H 


OH 


OH 
/        \0H 


OH 


Pyrocatechol 
(bitter) 


NH2 


\        . 

I 

1 
/COOH 

Ailthranilic  acid  (sweet) 


'OH 


Resorcinol 
(sweet) 


r' 


\ 


^OK 


Pyrogallol 
(bitter) 


SO: 


N 


NH 


CO^ 


Saccharin  (very  sweet) 


OH\        /OH 

\/        , 
Phloroglucinol 

(sweet) 


\ 


SO2 


CO-' 


)NH 


NH2 

(Very  sweet) 


./\ 


\ 


SO2 


>NH 


\/ 
Br 

(First  sweet,  then  bitter) 


\ 


CO' 


N02 

(Very  bitter) 


This  shows  that  the  arrangement  of  the  molecule  is  of  consider- 
able importance.  This  is  further  illustrated  by  the  differences  in 
the  taste  of  optical  isomers:  dextro-asparagin  is  sweet  while  levo- 
asparagin  is  not,  and  dextroglutaminic  acid  is  sweet  whereas  the 
levo  acid  is  tasteless. 

In  a  recent  study  of  the  chemistry  of  taste,  Oertly  and  Meyers^ 


'  Jour.  Am.  Chem.  Sdc,  1919,  xli,  p.  855. 


104  PHARMACOLOGY  OF  THE  CRANIAL  NERVES 

have  worked  out  a  theory  relating  to  the  ahphatic  sweet  stuffs. 
They  think  that  taste  is  dependent  on  two  factors — a  glucophoric 
and  an  auxoglue.  They  define  a  glucophore  as  a  group  of  atoms 
which  has  the  power  to  form  sweet  compounds  by  uniting  with  a 
number  of  otherwise  tasteless  atoms  or  radicals.  An  auxoglue  is 
defined  as  an  atom  or  radical  which  combined  with  any  of  the 
glucophores  yields  a  sweet  compound. 

The  following  radicals  are  found  to  be  glucophores  in  the  sense 
of  their  theory: 


-CO-CHOH-(+H), 

CHjOH-CHOH-. 

CO2H.CHNH2-, 

CH2ONO2- 

'"Hlx 

^Hs  -X  .  y^H2-y  — 

^Hlx       '"Hly 

Some  others  may  very  likely  be  included  later  on. 

The  following  atoms  or  radicals  seem  to  act  as  auxoglucs,  yielding 
with  glucophores  sweet  compounds: 

(a)  H,  hydrogen. 

(6)  The  radicals  CnH2n+l°  of  saturated  hydrocarbons,  contain- 
ing from  one  to  three  carbon  atoms.    Example,  CH3CH2. 

(c)  The  radicals  CnH2n+l°  of  monohydric  alcohols,  n  being 
equal  to  one  or  two.    Example,  CH2OH. 

(d)  The  radicals  CiiH2n— l°n  of  polyhydric  alcohols.  Example, 
CH2OHCHOH. 

Experiment. — Samples  of  the  various  drugs  may  be  tested  to 
determine  the  accuracy  of  the  above  statements. 

X.  The  Tenth  Nerve:  N.  Vagus. — The  vagus  is  a  mixed  nerve, 
with  a  wider  distribution  than  any  other  nerve  in  the  body.  It 
sends  sensory  nerves  to  the  mucous  membranes  of  the  larynx, 
trachea,  lungs,  esophagus,  stomach,  intestines,  gall-bladder  and 
ducts.  It  sends  motor  fibers  to  some  small  intrinsic  striated  muscles 
of  the  larynx  and  unstriated  muscles  of  the  heart,  lungs  and  intestine. 
From  the  pharmacological  standpoint  these  last  are  the  most  impor- 
tant, and  from  this  point  of  view  it  is  mainly  an  autonomic  nerve 
and  the  most  important  of  the  autonomic  nerves. 

The  action  of  drugs  on  the  vagus  endings  has  been  studied  under 
autonomic  drugs,  atropin  and  pilocarpin,  the  glands,  the  heart  and 
intestines. 

Nicotin  first  stimulates  and  then  paralyzes  the  ganglia  on  the 
vagus. 

The  vagus  center  is  stimulated  by  strychnin,  picrotoxin,  digitalis, 
epinephrin,  atropin,  by  asphyxia  and  high  blood-pressure.     The 


THE  OPTIC  NERVE  105 

center  is  depressed  by  morphin,  the  alcohol-chloral  groups,  bromides, 
etc.    See  experiments  under  Heart,  Autonomic  Drugs,  etc. 

XI.  The  Eleventh  Nerve :  N.  Acessorius. — This  is  a  motor  nerve 
supplying  the  sternomastoid  and  trapezius  muscles. 

XII.  The  Twelfth  Nerve :  N.  Hypoglossus. — The  twelfth  nerve  is 
a  motor  nerve  supplying  the  muscles  of  the  tongue,  the  extrinsic 
muscles  of  the  lar\iix  and  hyoid  bone. 

The  pharmacology  of  these  nerves  is  unimportant,  and  if  involved 
could  be  influenced  only  in  a  manner  similar  to  other  voluntary 
nerves.  The  centers  would  be  stimulated  by  strychnin,  caffein, 
etc.,  and  depressed  by  morphin  and  the  alcohol-chloral  group. 


CHAPTER  VII. 

PHARMACOLOGY  OF  THE  HEART  AND  BLOOD- 
PRESSURE. 

Factors  concerned  in  the  maintenance  of  blood-pressure: 
L  The  amount  and  the  condition  of  the  fluid  in  the  circulatory 
system.    The  amount  is  about  one-thirteenth  of  the  body  weight. 

2.  The  viscosity  of  the  blood,  or  rather  its  colloidal  condition, 
has  an  important  part  to  play.  It  is  well  known  that  injected  saline 
will  not  sustain  the  pressure  as  well  as  6  per  cent,  gum  acacia  or 
other  colloidal  solution.  Even  homogeneous  blood  beyond  a  defi- 
nite volume  will  not  remain  in  the  bloodvessels  any  length  of  time. 
Magnus  found  that  20  to  50  per  cent,  of  the  volume  of  such  injections 
left  the  vessels  and  was  expressed  into  the  tissues  within  three  to 
five  minutes  after  the  infusion. 

3.  The  peripheral  resistance — due  to  size  of  vessels  and  condi- 
tion of  muscle  tone. 

4.  The  condition  of  the  heart  itself. 

A  certain  blood-pressure  seems  necessary  for  the  life  and  func- 
tioning* of  protoplasm.  This  is  vividly  manifested  in  the  kidney 
which  stops  secreting  when  the  pressure  reaches  40  mm.  of  mercury. 
In  experimental  work  the  condition  of  the  fluid,  as  to  volume 
amount  and  to  some  extent  its  viscosity,  can  be  varied  at  will  and 
the  effect  studied.  The  peripheral  resistance  can  also  be  modified 
mechanically  and  by  the  action  of  drugs.  Drugs  which  increase  the 
tone  of  the  muscles  either  directly  or  indirectly  will  tend  to  increase 
blood-pressure.  Drugs  like  nicotin,  epinephrin  and  digitalis  that 
constrict  the  vessels  will  raise  the  pressure,  while  nitrites,  peptones, 
etc.,  that  dilate  the  vessels  will  lower  the  pressure. 

The  following  drugs  stimulate  the  heart  either  directly  or  through 
the  nerves,  and  therefore  tend  to  raise  the  blood-pressure : 

Caff  e  in. 

Strychnin. 

A  tropin. 

Cocain. 

Nicotin. 

Epinephrin. 

Pituitrin. 

Ca,  Ba,  Pb,  and  other  heavy  metals. 


BLOOD-PRESSURE  107 

Heart  depressants,  which  directly  or  indirectly  weaken  the  heart 
muscle,  reduce  the  tone  of  the  muscle  and  lower  the  blood-pressure: 
Aconite. 

The  alcohol  group. 
Nitrites. 
Study  the  mechanism  of  the  action  of  these  on  the   heart  and 
vessels  under  these  various  drugs.  s 


BLOOD-PRESSURE. 

The  action  of  drugs  on  the  blood-pressure  is  so  important  that  the 
following  summary  of  the  main  causes  affecting  the  blood-pressure 
are  given. 

Blood-pressure  may  be  lowered  by: 
I.  Slow  action  of  the  heart.    This  may  be  due  to: 

A.  Stimulation  of  the  vagus  center,  fibers,  or  endings  in  the 

heart. 
(a)  Directly  by  the  action  of  a  drug. 
(6)  Indirectly  by  increased  blood-pressure. 
(c)  Indirectly  by  increase  in  the  carbon  dioxide  con- 
tent of  the  blood. 
(fZ)  Reflexly  by  stimulation  of  any  sensory  nerve. 
II.  Increased  excitability  of  the  vagus  endings  in  the  heart. 
(a)  By  drugs. 
(6)  By  toxins. 

(c)  By  changes  in  the  function  of  ductless  glands. 

(d)  Indigestion,  products  of. 

III.  Paralysis  of  sympathetic  neurons — roots,  fibers  or  endings. 

IV.  Weakness  of  the  heart  muscle  from  any  cause. 

B.  Smallness  of  the  amount  of  blood  sent  out  at  each 

systole;  due  to 
(a)  Hemorrhage. 
(6)  Shock. 

(c)  Contraction  or  obstruction  of  pulmonary  vessels. 
{d)  Great  dilation  of  the  venous  system. 
(e)  Decompensated  heart. 

C.  Dilation  of  the  small  arteries.    This  would  be  difficult 

to  disassociate  from  dilation  of  the  capillaries. 

It  would  occur 
(a)  By  paralysis  of  the  vasoconstrictor  center. 
(h)  By  paralysis  of  the  arterial  walls. 


108     PHARMACOLOGY  OF  HEART  AND  BLOOD-PRESSURE 

Both  of  these  may  be  due  to  the  action  of  drugs  or  toxins  directly, 
or  reflexly  through  the  depressor  nerve,  division  of  the  cord  or 
section  of  the  splanchnics,  ablation  of  the  brain  or  great  depression 
of  the  brain  by  opiates  or  narcotics. 


SUBCL.   ART. 

R.VERT 


SYM.   TH.ORAC. 


Fig.  20. — Diagram  of  last  cervical  and  first  thoracic  ganglia  in  the  dog. 
(After  Foster.) 


Blood-pressure  may  be  increased  by: 

A.  By  quick  action  of  the  heart: 

(a)  By  paralysis  of  any  part  of  the  vagus  mechanism. 
(6)  Stimulation  of  the   sympathetics. 

Either  of  these  conditions  may  be  caused  directly  by  drugs. 
Atropin  will  paralyze  the  vagus.  Epinephrin  will  stimulate  the 
sympathetics.  Nicotin  will  first  stimulate,  later  paralyze  all 
ganglion  cells. 

B.  (a)  By  the  heart  expelling  a  larger  amount  of  blood  at  each 

beat,  as  after  the  administration  of  digitalis. 

(b)  Hypertrophied  heart. 

(c)  Increased  tone  of  the  heart  muscle. 

C.  By  contraction  of  the  small  arterioles  and  capillaries: 

(a)  By  irritation  of  the  vasoconstrictor  center. 

1.  Directly  by  drugs  or  toxins. 

2.  Indirectly  by  carbon  dioxide  accumulation  in  the 

blood. 


DIGITALOID  DRUGS  AND  DIGITALIS 


109 


3.  Reflexly  through  the  cervical  sympathetic. 

4.  Reflexly  through  other  nerves,  e.  g.,  the  vagus  in 

non-anesthetized  animals. 

5.  Reflexly  through  any  sensory  nerves. 
(6)  Direct  stimulation  of  the  vascular  walls. 

1.  By  drugs. 

2.  In  operations  where  the  peripheral  ends  of  vaso- 

constrictor nerves  are  stimulated. 
D.  By  conditions  which  increase  the  tone  of  the  skeletal  muscles. 


Fig.  21. — Suspension  method  of  recording  heart  contractions. 


DIGITALOID  DRUGS  AND  DIGITALIS. 

The  main  actions  of  the  digitaloid  drugs  are: 

1.  A  specific  stimulating  action  on  the  heart  which  renders  it 
more  irritable,  with  a  tendency  to  more  rapid  action. 

2.  Stimulation  of  the  vagus  center  which  tends  to  slow  the  heart. 

3.  Stimulation  of  the  vasoconstrictor  center. 

4.  Direct  stimulation  of  the  musculature  of  the  vessels  particu- 
larly strong  in  the  splanchnic  region,  with  a  tendency  to  lessen  the 
secretion  of  urine. 

5.  An  irritant  action  on  the  stomach  or  wherever  applied;  this 
cau.scs  vomiting  when  taken  into  the  stomach  in  large  quantities 
and  pain  when  applied  to  mucous  membrane. 


110     PHARMACOLOGY  OF  HEART  AND  BLOOD-PRESSURE 

6.  A  direct  stimulating  action  on  the  vomiting  center.  (Hatcher.) 

7.  A  tonic  action  on  the  central  nervous  system. 

8.  A  tonic  action  on  endothelial  and  lymphatic  tissues. 

9.  A  marked  diuretic  action  in  cases  of  edema  through  changes 
in  the  circulation. 


Fig.  22. — Suspension  method  of  recording  heart  tracings. 


Experiment  I. — Action  on  the  Frog  or  Turtle  Heart:  Isolate  the 
vagus;  take  a  tracing  of  the  normal  heart  by  the  suspension  method. 
Stimulate  the  vagus.  Apply  a  few  drops  of  an  infusion  of  digitalis 
to  the  exposed  heart.  This  may  be  repeated  every  five  minutes 
until  the  heart  stops  in  ventricular  systole.  Study  the  action  of 
the  vagus  every  ten  minutes  and  record  its  effect  at  the  different 
stages  of  digitalis  action. 

Experiment  II. — Prepare  several  turtle  heart  strips  and  take  trac- 
ings in  the  usual  way.    When  the  strips  beating  are  regularly  place: 

1.  In  a  bath  of  0.002  per  cent,  digitalis  in  saline. 

2.  In  a  bath  of  0.005  per  cent,  digitalis  in  saline. 

3.  In  a  bath  of  0.01  per  cent,  digitalis  in  saline. 
Compare  results. 

Experiment  III. — Place  a  cannula  in  the  vena  cava  of  a  frog 
(Figs.  23  and  24),  or  turtle  and  perfuse  with  0.001  per  cent,  digi- 
talis in  Ringer's  solution.  What  is  the  effect  on  the  heart  beat? 
Take  tracing. 

Experiment  IV, — Action  of  Digitalis  on  the  Heart  and  Respiration 
of  a  Dog. — 1.  Weigh  animal  and  record  pulse  and  respiration-rate, 
general  appearance  and  condition. 


DIGATALOID  DRUGS  AND  DIGITALIS 


111 


Cannula  connected 
to    aorta 


Capillar//  catheter  in  median 
uhdominal  vein 


Fkj.  23. — Frog-perfusion  method,  to  study  action  of  drugs  on  vessels.     (Fuehner.) 


Fio.  24. — Fuehner  apparatus  arranged  for  perfusion. 


112     PHARMACOLOGY  OF  HEART  AND  BLOOD-PRESSURE 

2.  Inject  slowly  into  the  femoral  vein  0.4  c.c.  per  kilogram  of 
1  per  cent,  infusion  of  digitalis  without  anesthesia. 

3,  Record  observations  as  in  1  every  five  minutes. 
Experiment  V. — Action  of  Digitalis  on  the  Heart  and  Respiration. 

■ — 1.  Record  weight,  heart-rate  and  respiration  of  a  dog. 

2.  Anesthetize  in  the  usual  way;  isolate  one  vagus  nerve;  ligate 
cut  and  prepare  peripheral  and  central  ends  for  stimulation. 

3.  Arrange  for  blood-pressure  and  respiration  tracings. 

4.  Take  normal  tracings  and  show  the  influence  of  vagus  stimula- 
tion, central  and  peripheral.    Also  similar  stimulation  of  the  sciatic. 

5.  Slowly  inject  into  the  femoral  vein  0.2  c.c.  of  1  per  cent, 
infusion  of  digitalis  per  kilogram. 

6.  Stimulate  vagus  and  sciatic  as  in  4. 

7.  Repeat  5. 

8.  Stimulate  vagus  and  sciatic  as  in  4. 

9.  Repeat  5  if  thought  advisable. 

Experiment  VI. — Demonstration;  Myocardiagram  and  Blood- 
pressure  under  Digitalis. — 1.  Anesthetize  a  dog  with  ether.  Prepare 
for  blood-pressure  and  myocardiagraph  tracings;  superimpose  the 
tracings. 

2.  Inject  slowly  0.4  c.c.  of  1  per  cent,  infusion  of  digitalis  per 
kilogram  of  body  weight  into  the  femoral  vein  and  take  continuous 
tracing.    In  thirty  minutes  repeat  the  dose  if  necessary. 

Experiment  VII. — Digitalis  as  a  Diuretic— 1.  Weigh  and  anes- 
thetize a  dog.  Prepare  for  blood-pressure  tracing.  Insert  a  catheter 
into  the  bladder  and  measure  secretion  of  urine  in  drops  for  thirty 
minutes. 

2.  Inject  0.5  c.c.  of  1  per  cent,  infusion  of  digitalis  into  the  femoral 
vein  every  five  minutes  for  four  or  five  times  or  until  the  animal 
gets  about,  0.4  c.c.  per  kilo.  Note  the  effect  on  the  urine  for  thirty 
minutes. 

3.  Inject  1  c.c.  per  kilo  of  2  per  cent,  theobromin  sodium  salicylate 
and  compare  the  urine  secretion  with  that  of  digitalis  for  thirty 
minutes. 

Experiment  VIII. — Standardization  of  Digitalis.  Digitalis;  Stro- 
phanthus;  Squill. — For  the  physiological  standardization  of  this 
series  the  "one-hour  frog"  method  is  recommended.  The  method 
consists  in  ascertaining  the  dose  of  the  drug  or  preparation  that  will 
bring  the  heart  of  a  frog  weighing  15  to  25  grams  to  systolic  stand- 
still in  one  hour.  All  measurements  in  the  operation  should  be 
carried  out  with  the  same  degree  of  accuracy  used  in  quantitative 
chemical  estimations. 


DIGATALOID  DRUGS  AND  DIGITALIS 


113 


Frog:   Use  healthy  specimens  weighing  between  15  and  25  grams. 

Storage:  The  animals  should  be  kept  in  a  cool  room,  preferably 
where  the  temperature  does  not  rise  above  15°  C.  The  bottom  of 
the  tanks  should  be  covered  with  running  water,  or,  if  this  is  not 
convenient,  the  water  in  the  tank  should  be  changed  four  times  daily. 

An  hour  before  the  animals  are  used  they  should  be  kept  in 
the  laboratory  in  order  to  get  acclimated  to  temperature.  Weigh 
within  1  gram. 


Fig.  25. — Figures  showing  the  lymph  sacs  of  the  frog  as  seen  from  the  ventral  surface. 
Lymph  sacs  as  seen  from  the  side.  For  pharmacological  purposes  these  sacs  need 
not  be  named,     (.\fter  Ecker.) 


Dosage:  Never  inject  more  than  0.015  c.c.  for  each  gram  of 
frog.  A  larger  volume  than  this  is  injurious  from  the  volume  alone. 
No  attention  need  be  paid  to  the  alcoholic  content  unless  this  is 
over  20  per  cent,  of  the  injected  material.  In  such  cases  evaporate 
the  alcohol  on  a  water-bath  and  dilute  or  make  up  volume  with 
0.07  per  cent,  sodium  chloride:  if  there  is  a  cloudiness  or  a  precipi- 
tate, shake  the  solution  before  injecting.  Injections  should  be 
made  through  the  floor  of  the  mouth  into  the  anterior  lymph  sac 
8 


114     PHARMACOLOGY  OF  HEART  AND  BLOOD-PRESSURE 

with  a  hypodermic.  Do  not  puncture  the  skin,  because  there  may 
be  a  leakage.  Since  the  dose  of  a  standard  preparation  of  digitalis 
tincture  is  0.006  c.c.  per  gram  weight  of  frog,  the  first  trial  should 
vary  from  0.004  c.c.  to  0.008  c.c.  per  gram.  At  the  end  of  an  hour 
the  frogs  should  be  pithed,  both  brain  and  cord,  and  the  heart 
examined.  For  the  correct  end-reaction  the  ventricle  is  stopped 
in  systole  and  the  auricles  dilated.  If  these  are  stimulated  there 
may  be  feeble  contraction,  but  no  general  contractions  is  allowed. 
After  this  preliminary  trial  one  knows  approximately  what  the 
standard  dose  is;  for  instance,  it  may  be  between  0.005  and  0.006 
or  between  0.006  and  0.007.  Another  trial,  working  with  dilutions 
between  these  figures,  will  determine  the  dosage  accurately.  The 
U.  S.  P.  adopts  the  following  as  standard  doses: 

Gram  or  milliliter 

for  each  gram  of 

body  weight  of 

frog. 

Standard  dose  of  ouabain 0 .  0000005 

Digitalis:   Leaves  (in  the  form  of  tincture) 0.0006 

Fluidextract 0.0006 

Tincture 0.006 

Strophanthus :    Seed  (in  the  form  of  tincture) 0.000006 

Tincture        0.00006 

Squill:   Dried  squill  (in  the  form  of  tincture) 0.0006 

Fluidextract 0.0006 

Tincture 0.006 

Experiment  IX. — Hatcher's  Cat  Method  of  Standardizing  Digitalis. 
— One  milligram  of  crystallin  ouabain  or  100  mg.  of  digitalis  per 
kilogram  of  body  weight  when  introduced  slowly  intravenously 
will  kill  a  cat  in  about  an  hour.  Not  less  than  an  hour  should  elapse 
in  the  injection  or  the  method  is  not  advised.  Hatcher  recommends 
the  following  procedure: 

Anesthetize  an  animal  with  ether  and  place  a  cannula  into  the 
femoral  vein  for  injection  from  a  burette.  The  preparation  to  be 
injected  is  diluted  with  normal  salt  solution  to  such  a  strength  that 
roughly  10  c.c.  of  the  dilution  per  kilogram  are  required  to  cause 
death  under  the  conditions  of  the  experiment  (1  c.c.  of  tincture  plus 
9  c.c.  of  normal  saline).  The  injection  is  made  slowly  and  con- 
tinuously into  the  femoral  vein  of  the  cat  at  such  a  rate  that  1  per 
cent,  of  the  fatal  dose  is  injected  in  a  minute  of  time  until  toxic 
symptoms  develop,  when  the  injection  is  interrupted  for  ten  minutes. 
If  death  does  not  occur  the  injection  is  resumed  at  the  same  rate 
as  before  and  continued  until  the  symptoms  show  the  approach  of 
death.  If  preferred,  about  half  of  the  fatal  dose  may  be  injected 
within  a  period  of  fifteen  minutes,  after  which  the  injection  is  inter- 
rupted for  ten  minutes  and  then  continued  at  the  rate  of  about  1 


STANDARDIZATION  OF  SUPRARENAL  GLAND  115 

per  cent,  of  the  estimated  fatal  dose  per  minute  until  the  appearance 
of  toxic  symptoms,  when  the  injection  is  interrupted,  as  already 
mentioned. 

Experiment  X. —  TJie  Gold  Fish  Method  of  PiUinger  and  Van  der 
Kleed. — Demonstration:  Pittinger  and  Van  der  Kleed^  have  advo- 
cated the  use  of  gold  fish  instead  of  frogs  as  a  method  of  standardiza- 
tion of  digitalis.  The  method  has  never  been  completely  developed. 
The  advantages  claimed  were  simplicity  and  cheapness,  but  the 
latter  does  not  hold  now.  The  size  of  the  fish  is  unimportant  because 
the  absorbing  surface  of  the  gills  corresponds  in  all  sizes.  The  fol- 
lowing protocol  taken  at  27.5°  C.  will  illustrate  the  method.  The 
best  temperature  to  employ  still  remains  to  be  determined.  In  the 
following  experiment  eight  fish  were  placed  in  beakers,  each  contain- 
ing the  same  strength  of  solution  in  order  to  determine  the  individual 
variation  in  susceptibility  to  digitalis. 

Time  required  to 
Dilution  of  Weight  of  fish,  cause  death, 

fluidextract.  grams.  Temperature.  Minutes 

1  to  1000 34.1  27.5°  58 

1  to  1000 27.9  27.5°  52 

1  to  1000 5.5  27.5°  59 

1  to  1000 5.0  27.5°  47 

1  to  1000 2.3  27.5°  54 

1  to  1000 3.1  27.5°  55 

Experiment  XL — Students  should  divide  in  groups  and  group: 

1.  Take  1  c.c.  tincture  of  digitalis  every  four  hours  for  six  times. 

2.  Take  2  c.c.  tincture  of  digitalis  every  four  hours  for  six  times. 

3.  Take  3  c.c.  tiiicture  of  digitalis  every  four  hours  for  three  times. 

4.  Take  4  c.c.  tincture  of  digitalis  in  one  dose. 

Record  pulse,  respiration  and  general  condition  for  forty-eight 
hours. 

STANDARDIZATION  OF  SUPRARENAL  GLAND. 

This  method  depends  on  the  experimental  findings  that  1  gram 
of  dried  suprarenal  gland  will  raise  the  blood-pressure  of  a  dog  to 
the  same  degree  as  10  mg.  of  levo-methyl-amino-ethanol-catechol. 

Standard  Solution. — 1.  Prepare  an  aqueous  solution  of  levo- 
methyl-amino-ethanol-catechol  (1  to  1000),  using  enough  dilute 
hydrochloric  acid  to  get  a  clear  solution.  From  this  solution 
prepare  a  solution  of  1  to  100,000  by  diluting  1  c.c.  up  to  100 
with  0.9  per  cent,  sodium  chloride. 

2.  Weigh  out  1  gram  of  finely  divided  j)owder  of  suprarenal  gland. 
Macerate  twenty-four  hours  in  100  c.c.  of  distilled  water,  containing 

'  Jour.  Am.  Pharni.  A.smii.,  I!il5,  p.  427. 


116     PHARMACOLOGY  OF  HEART  AND  BLOOD-PRESSURE 

10  c.c.  dilute  hydrochloric  acid  (10  per  cent.),  shaking  frequently. 
Filter  through  a  dry  filter. 

Dogs. — Use  a  medium-size  animal.  Anesthetize  with  ether. 
Insert  cannula  in  carotid  for  blood-pressure  estimation.  Insert 
cannulse  in  each  femoral  vein  and  connect  with  a  burette  with  a 
rubber,  so  that  injections  may  be  made.  Injections  should  be  made 
with  glass  syringes  graduated  to  0.05  c.c.  The  animal  should  be 
kept  deeply  anesthetized,  and  if  there  is  any  twitching  sufficient 
curare  should  be  injected  to  prevent  this.  Usually  this  is  not  needed. 
Take  blood-pressure  on  a  long  kymograph. 

Inject  1  c.c.  of  the  standard  solution  and  wash  in  with  saline. 
Note  the  height  of  the  pressure.  After  five  minutes  inject  1  c.c. 
of  the  gland  or  solution  to  be  tested.  Wait  five  minutes  between 
each  injection  and  change  the  dose  of  one  or  the  other  solutions 
until  the  blood-pressure  rise  is  the  same.  In  this  way  the  strength 
of  the  unknown,  in  terms  of  the  standard,  may  be  ascertained. 

ACONITIN. 

The  active  principle  of  aconite  is  aconitin. 

Aconitin  is  an  alkaloid,  peculiar  from  the  fact  that  it  stimulates 
sensory  nerve-endings — those  of  common  sensation,  even  when  it  is 
given  systemically.  The  only  other  drug  that  does  this  is  veratrin. 
It  has  a  similar  action  if  applied  locally. 

The  maiji  actions  of  aconitin  are: 

1 .  A  prickling,  tingling  sensation  due  to  an  action  on  the  terminal 
sensory  nerves.    Large  doses  may  cause  paralysis  of  these  endings. 

2.  Depression  of  the  heart  due  to  central  vagus  stimulation — 
maybe  followed  by  paralysis. 

3.  Stimulation  and  paralysis  of  all  medullary  centers. 

4.  A  complicated  action  on  the  heart. 

(a)  There  may  be  acceleration  due  to  nausea  and  to  gastric 
irritation. 

(6)  Slowing  due  to  stimulation  of  the  vagus  center. 

(c)  Quicker  heart  from  direct  action,  and  fatigue  of  vagus  centers. 

(d)  Irregularities  from  poisoning  of  the  heart  muscle,  which  may 
pass  into  fibrillation. 

(e)  In  the  frog's  heart,  aconitin  when  applied  directly  may  cause 
(1)  slowing,  (2)  quickening,  (3)  slowing,  (4)  quickening. 

1.  Due  to  vagus  stimulation  of  vagus-endings. 

2.  Due  to  muscular  stimulation. 

3.  Incoordination  leading  to  paralysis. 

4.  Complete  incoordination  passing  into  fibrillation  or  peristalsis. 


ACONITIN 


117 


This  peristalsis  is  characteristic. 

(/)  Aconitin  is  a  general  protoplasmic  poison,  but  it  will  kill  from 
a  central  action  before  this  is  seen. 

Experiment  I. — (a)  Inject  0.5  c.c.  of  0.1  per  cent,  aconitin  into  the 
lymph  sac  of  a  frog  (Fig.  25).    Compare  this  with  another  frog: 

(b)  Into  which  0.5  c.c.  of  5  per  cent,  infusion  of  digitalis  is  injected 
in  the  same  way. 


VOLUNTARY 
MOVEMENT  LOST 


UNABLE  TO  RECOVER 
POSITION  WHEN 
LAID  ON  ITS  BACK 


SCIATIC  NERVE 


Fig.  26. — To  show  location  of  different  parts  of  the  brain  and  effects  of  their 
ablation,  also  the  location  of  the  sciatic  nerve  and  the  gastrocnemius  muscle.  (Modi- 
fied from  Dixon.) 


Experiment  H. — Pith  a  frog  and  take  heart  tracings  by  the  sus- 
pension method.  Inject  1  c.c.  of  0.1  per  cent,  aconitin  into  the 
anterior  lymph  sac  and  take  continuous  tracings  until  the  heart 
is  paralyzed. 

Experiment  m. — Take  a  continuous  tracing  of  the  blood-pressure 
and  respiration  of  a  dog.  Give  an  intravenous  injection  of  0.5  c.c. 
of  0.1  per  cent,  aconitin  every  ten  minutes  until  the  animal  dies. 
Keep  a  cfjinj^lete  record  of  the  symptoms. 

Experiment  IV. — Count  respiration  and  heart-rate  of  a  dog.  Give 
1  c.c.  of  0.1  i>er  cent,  aconitin  intravenously  without  anesthesia 
and  record  result  on  heart-rate,  resi)iration  and  general  condition. 


118     PHARMACOLOGY  OF  HEART  AND  BLOOD-PRESSURE 

Experiment  V. — Squibb's  Test  for  Aconitin. — Dilute  tincture  of 
aconitin  1  to  70.  Hold  4  c.c.  of  this  in  the  anterior  of  the  mouth  for 
one  minute  and  discharge  it.  A  distinct  tingling  will  be  apparent 
in  from  ten  to  fifteen  minutes.  Note  that  the  aconitin  group  of 
drugs  is  the  only  one  which,  when  taken  systemically,  has  a 
selective  action  on  the  sensory  nerves. 

Experiment  VI. — The  Bio-assay  of  Aconitin. — Method,  U.  S.  P., 
ix,  p.  606.  The  method  of  the  physiological  assay  of  aconitin  con- 
sists in  determining  the  minimum  lethal  dose  for  guinea-pigs. 

Method. — Select  guinea-pigs,  250  to  350  grams  weight,  in  a 
healthy  condition. 

Drug. — The  tincture,  extract  or  fluidextract  may  be  used. 

Administration. — The  drug  is  administered  hypodermically.  If 
the  extract  is  used  it  must  be  prepared  in  a  liquid  form  suitable  for 
injection.  After  injection  the  animals  are  placed  in  cages  and  in 
twelve  hours  note  is  taken  of  those  living  and  dead. 

Standard. — The  standard  fatal  dose  is  as  follows: 

Fluidextract 0.00004  c.c.  per  kilo  of  body  weight. 

Tincture 0.0004    c.c.  "  " 

Extract 0.00001  gm.  "  " 

In  making  the  test  a  series  of  animals  is  used,  varying  the  dose 
on  each  side  of  the  standard  dose  until  the  dose  of  the  preparation 
to  be  determined  is  ascertained. 

THE  NITRITES. 

The  important  action  of  the  nitrites  is  on  the  circulation. 

Experiment  I. — Action  of  Nitrites  on  the  Circulation  and  Respira- 
tion.— (a)  Anesthetize  an  animal  and  prepare  for  blood-pressure 
and  respiratory  tracings.  Place  a  cannula  in  the  femoral  vein  for 
intravenous  injections.  Isolate  the  vagus,  stimulate  and  take 
tracing. 

(fe)  While  taking  normal  tracings  let  the  animal  inhale  a  little 
amyl  nitrite  through  the  trachea.  Allow  the  pressure  to  become 
normal.  Stimulate  the  vagus  and  let  the  animal  again  inhale  amyl 
nitrite,  and  when  pressure  is  at  the  lowest  point  again  stimulate 
the  vagus. 

(c)  Inject  1  to  10,000  epinephrin;  note  the  height  to  which  the 
pressure  rises,  and  when  the  pressure  is  high  again  stimulate  the 
vagus.  Study  the  activity  of  the  vagus  at  high  and  low  pressures. 
Continue  the  administration  of  amyl  nitrite  as  in  (6)  and  note 
whether  or  not  it  is  as  effective  after  several  exhibitions. 


THE  NITRITES  119 

(d)  Take  a  sample  of  blood  and  note  the  color— methemoglobin. 
Study  with  the  spectroscope. 

(e)  ^Mien  amyl  nitrite  fails  to  cause  a  reduction  of  pressure, 
mject  1  c.c.  of  1  to  10,000  epinephrin  and  compare  the  height  to 
which  the  pressure  rises  with  that  of  the  injection  under  (c). 

Experiment  II.— Prepare  animal  as  in  1.  In  this  experiment  use 
nitroglycerin. 

(a)  Take  normal  tracings.  Inject  1  c.c.  of  1  to  10,000  epinephrin; 
when  the  pressure  is  normal,  inject  1  c.c.  of  0.1  per  cent,  nitroglycerin 
intravenously.    Isolate  and  stimulate  the  vagus. 

(6)  Repeat  injections  of  nitroglycerin  until  the  effect  is  relatively 
small.  It  may  be  advisable  to  double  the  dose  of  the  nitrite  in  the 
latter  injections. 

(c)  Examine  the  blood  with  spectroscope  (see  Figs.  55  and  56.) 

(d)  Stimulate  the  vagus  when  pressure  is  at  its  lowest  and  com- 
pare with  the  initial  effect. 

(e)  \Mien  the  pressure  falls  but  little  on  administration  of  the 
nitrites  give  1  c.c.  of  1  to  10,000  epinephrin  and  compare  with  the 
first  effect.  If  epinephrin  fails  to  act  or  is  much  weaker  in  its 
action,  how  is  it  to  be  explained? 

Experiment  m.— Repeat  Experiment  II,  using  0.1  per  cent, 
sodium  nitrite,  giving  0.5  to  1  c.c.  intravenous  doses. 

Experiment  IV.— Anesthetize  a  dog  and  prepare  for  records  as  in 
Experiment  I.  Take  normal  records.  Give  the  animal  1  c.c.  of  0.5 
per  cent,  atropin.  Repeat  1.  After  atropin,  compare  results  with 
those  in  which  atropin  was  not  used. 

Experiment  V.— Students  may  experiment  on  themselves  as 
follows:  (a)  In  sitting  position  with  arm  on  the  table,  take  the 
normal  pulse  record  with  a  standard  sphygmograph. 

(b)  Break  an  amyl  nitrite  pearl  in  the  handkerchief  and  inhale 
the  fumes. 

(c)  Take  pulse  tracings  again,  immediately,  in  five  minutes  and 
in  ten  minutes.  Study  the  effects  which  follow  the  use  of  amyl 
nitrite. 

Experiment  71.— Action  of  Nitrites  on  /Vof/.?. —Inject  into  the 
lymph  .sac  of  frog  number: 

1.  0.5  c.c.  of  0.1  per  cent,  nitroglycerin. 

2.  0.5  c.c.  of  0.1  per  cent,  amyl  nitrite. 

3.  0.5  c.c.  of  1.0  per  cent,  sodium  nitrite. 
Record  the  eft'ects. 

Experiment  Vn. — Injluence  of  Nitritefi  on  the  Bloodvessels'.  Per- 
fusif/n    Experiments;    Lewen-Trendelenhirg   Method  (Ings.  2.3    and 


120     PHARMACOLOGY  OF  HEART  AND  BLOOD-PRESSURE 

24).  Pith  a  frog  or  small  turtle.  Fix  to  board.  Tie  a  fine 
cannula  in  the  aorta  for  perfusion;  insert  a  fine  cannula  in  the 
large  median  abdominal  vein.  Perfuse  with  Ringer's  solution 
through  the  aorta  and  count  the  drops  from  the  vein.  If  it  is  diffi- 
cult to  get  a  cannula  in  this  vein,  so  that  you  fail,  cut  the  vein  and 
elevate  the  animal  and  the  drops  may  be  counted  without  the 


Fig.  27. — Arrangement  of  apparatus  for  recording  contractions  of  turtle  heart 
strip.  The  same  arrangement  will  do  for  uterine  strips  if  temperature  and  aeration 
are  controlled. 


Fig.  28. — Plethysmograph  for  the  study  of  changes  in  volume  of  the  arm. 


cannula.  "When  the  normal  is  obtained,  add  to  the  Ringer  solution 
enough  sodium  nitrite  solution  to  make  0.01  per  cent,  sodium 
nitrite  and  measure  the  change  in  the  rate  of  flow  either  in  drops 
per  minute  or  in  volume. 

Experiment  Vm. — ^Action  of  sodium  nitrite  on  the  contracting 
ventricular  strip  may  be  demonstrated  as  follows:    Set  up  a  strip 


PLATE  IV 


Danger  area 


3.  Hespiratlon  paralyzed 


4,  Circulation  pai'ali/zed 


Anesthesia  area 

1.  Consciousness  abolished 


2.  Jteflex  activity  abolished 


The  several  sections  are  numbered  iu  the 
order  in  which  they  are  paralyzed  by  anes- 
thetics. The  paralysis  of  1  and  2  constitutes 
surgical  anesthesia,  paralysis  of  3  introduces 
an  element  of  great  danger,  and  that  of  4  is 
usually  fatal. 

[The  heart  is  included  iu  this  diagram  of 
the  .several  parts  of  the  central  nervous  sys- 
tem, for  the  reason  that  it  contains  nerve- 
ganglia,  which,  with  their  highly  i.-ritable 
muscular  structure,  provides  for  its  auto- 
matic, rhythmic  action.  This  provision  is 
unite  independent  of  the  cerebrospinal  sys- 
tem.] 


ACTION  OF   THE  ALCOHOL  CHLORAL  GROUP 


121 


and  take  a  normal  tracing.  When  the  strip  beats  rhythmically 
add  0.02  per  cent,  sodium  nitrite  (Fig.  27).  What  is  the  proof 
that  nitrites  act  on  the  vessel  wall  directly?  Compare  the  action 
of  epinephrin,  ergot,  nitrites  and  barium  on  the  bloodvessels. 

Experiment  IX.— Take  a  normal  tracing  with  the  arm  in  a  ple- 
thysmograph  (Fig.  28).  After  five  minutes  break  and  inhale  a 
three-  or  five-minim  ampoule  of  amyl  nitrite  and  again  record  for 
five  minutes. 


THE  ACTION  OF  THE  ALCOHOL  CHLORAL  GROUP  ON  THE 
PUPIL,  HEART  AND  REFLEXES. 

On  two  series  of  frogs,  perform  the  following  experiments,  noting 
especially  the  condition  of  the  reflexes,  the  size  of  the  pupil  and  the 
condition  of  the  heart  at  the  end  of  the  experiment.  One  group  of 
students  will  work  with  one  series  of  frogs  and  the  second  group 
with  the  second  series,  taking  care  to  select  specimens  for  both 
groups  of  about  the  same  size.  Injections  will  be  made  in  the 
anterior  lymph  sac.    The  dose  will  be  varied  as  follows: 


Frog  No 

1  . 

2  . 
.3  . 

4  . 

5  . 

6  . 


Group  I. 

1.00  c.c.  (25  percent.) 

0.10  c.c. 

0.50  c.c. 

0.25  c.c. 

0.50  c.c.  (10  per  cent.) 

0.50  c.c.  saturated 

water  solution 
1 .  00  c.c.  (2  per  cent.) 
1.00  c.c.  (4  per  cent.) 

Control 


Group  II. 
2.00  c.c.  (25  per  cent.) 
0.30  c.c. 
1.00  c.c. 
0.75  c.c. 

2.00  c.c.  (10  percent.) 
2 .  00  c.c.  saturated 

water  solution 
2.00  c.c.  (2  percent.) 
2.00  c.c.  (4  per  cent.) 
Pith  brain  and  cord. 


Drug. 
Alcohol. 
Chloroform. 
Ether. 

Paraldehyde. 
Ure  thane. 
Chloreton. 

Chloral. 
Morphin. 


At  the  end  of  one  hour  pith  all  the  animals,  expose  the  heart 
by  a  small  incision  and  make  record  tracings  of  each  on  the  same 
drum  for  comparison. 

State  the  condition  of  the  heart,  pupils  and  reflexes. 

Reflex  Time  as  Changed  by  Alcohol.— 1.  What  is  the  function  of 
reflexes? 

2.  Their  importance  in  every-day  life? 

3.  The  modification  of  reflexes  by  the  alcohol  group  of  drugs? 

4.  TIow  arc  reflexes  tested? 

Experiment  I.— Turck's  method  of  determining  reflex  time  (see  Fig. 
13.)  Pith  a  frog  waiting  twenty  minutes  for  recovery  from  shock  and 
suspend  it  })y  the  head  with  a  clamp.  With  a  small  beaker  contain- 
ing 0.5  per  cent.  IK'l  or  II2SO4  immerse  the  toe  or  foot  to  a  definite 
point.    Note  the  time  of  withdrawal  by  a  stop-wat(;h.    Wash  oft' 


122     PHARMACOLOGY  OF  HEART  AND  BLOOD-PRESSURE 

the  acid  with  another  beaker  containing  water.  Repeat  the  process 
until  five  concordant  results  are  obtained  and  take  the  average. 
Now  take  the  frog  from  the  position  and  inject  0.5  c.c.  of  25  per  cent, 
alcohol  into  the  anterior  lymph  sac.  In  fifteen  minutes  repeat  the 
determination  of  reflex  time.  Repeat  the  injection  of  alcohol  and 
the  determination  of  the  reflex  time  until  a  definite  change  is 
obtained. 

Experiment  II. — Crossed  Reflex  Time  (Fig.  29). — In  this  experi- 
ment the  possibUity  of  direct  stimulation  on  axon  reflexes  is  ruled 
out.    The  movement  when  obtained  is  decisively  reflex. 


^V~ 


Fig.  29. — Method  of  taking  crossed  reflex. 


Pith  a  frog  as  above.  Wait  fifteen  minutes  for  recovery  from 
shock.  Suspend  the  animal  by  the  head  with  a  muscle  clamp. 
Attach  the  toe  of  the  foot  to  a  muscle  lever  to  write  on  a  slowly 
moving  drum.  Arrange  a  signal  magnet  to  write  below  the  muscle 
curve.  Insert  thin  wire  electrodes  from  a  secondary  induction 
coil  into  the  skin  of  the  other  leg  and  tie  the  foot  so  that  this  leg 
cannot  move.  Adjust  the  induction  coil  to  produce  a  stimulus  that 
will  give  a  distinct  cross  reflex  movement.    Take  the  time  of  the 


ACTION  OF   THE  ALCOHOL  CHLORAL  GROUP 


123 


movement  with  a  stop-watch  or  from  a  time  mark  record  on  the 
drum.  Get  the  average  of  five  determinations.  Have  the  time  of 
these  determinations  sufficiently  far  apart  to  eUminate  the  prob- 
abihty  of  fatigue  playing  a  role.  When  the  normal  is  obtained  inject 
alcohol  0.5  c.c.  of  20  per  cent,  into  the  dorsal  lymph  sac  and  after 
ten  minutes  or  more  repeat  the  determination.  Repeat  injections 
of  alcohol  every  thirty  minutes  until  a  definite  change  in  the  reflexes 
is  obtained.  These  experiments  may  be  repeated,  using  3  to  5  drops 
of  ether,  3  drops  of  chloroform,  or  1  c.c.  of  2  per  cent,  chloral  hydrate. 


Fig.  30. — Arrangement  of  apparatus  for  recording  reflex  time.     (After  Jackson.) 


Experiment  HI. — Effect  of  Alcohol  on  the  Reaction  oj  the  Student. — 
The  following  experiment,  devised  by  Jackson,  will  show  the  change 
in  the  reaction  time  in  human  beings: 

1.  Reaction  of  sight  as  affectecf  by  alcohol.  Arrange  a  signal 
magnet  to  write  on  a  swiftly  moving  drum.  Connect  this  magnet 
with  a  cell  and  in  the  circuit  place  two  keys  or  switches.  When 
either  key  is  opened  the  circuit  is  broken  and  the  result  is  indicated 
on  the  drum .    Two  students  work  this  experiment. 

One,  the  operator,  holds  key  B,  while  the  other,  the  subject, 
whose  reaction  is  to  be  tested,  holds  key  A.  The  man  at  key  A 
keeps  his  attention  centered  on  the  signal  magnet,  which  is  writing 
on  the  swiftly  moving  drum.  The  operator  closes  key  B,  which 
causes  the  writing-point  of  the  signal  magnet  on  the  drum  to  fall. 
The  subject  opens  key  A  as  soon  as  he  sees  the  fall  of  the  writing- 
point.  While  the  drum  keeps  running,  B  is  opened  by  the  operator 
and  key  A  is  closed  by  the  subject  at  once. 

Key  B  is  again  closc.'d  and  A  opened,  etc.,  as  rapidly  as  the  sub- 


124     PHARMACOLOGY  OF  HEART  AND  BLOOD-PRESSURE 

ject  perceives  the  movement  of  the  needle  caused  by  the  opening  or 
closing  of  B  until  from  twenty  to  thirty  records  are  made. 

The  average  time  of  the  sight  reaction  is  obtained  as  follows: 
An  electric  tuning-fork,  vibrating  from  50  to  100  times  a  second, 
is  used  to  run  a  time  tracing  around  the  drum  parallel  to  the  reaction 
time  record.  A  rule  or  pair  of  dividers  is  used  to  measure  off  the 
time  for  each  reaction  and  an  average  for  normal  sight  reaction  is 
then  calculated. 

The  next  step  after  determining  the  time  for  normal  reaction  is 
to  determine  the  time  for  sight  reaction  after  alcohol  has  been 
administered.  Five  to  10  c.c.  of  alcohol  or  whisky  or  brandy,  well 
diluted  in  water,  and  sweetened  to  render  the  liquor  more  pala- 
table, are  taken  into  the  stomach  by  the  subject.  After  fifteen 
minutes  the  same  process  as  that  described  above  is  repeated  and 
the  results  of  the  two  tests  compared,  to  show  the  effect  of  alcohol 
on  the  time  reaction  of  sight. 

Ether  and  Chloroform  Anesthesia.^ — The  student  should  be  able  to 
explain  the  effect  and  the  nervous  mechanism  in  each  case. 

The  symptoms  are  conveniently  divided  into  four  stages: 
I.  Preliminary   or   Stage   of    Disorganized   Consciousness   and 
Analgesia. — Struggling  due  to: 

1.  Irritant  action  on  mucous  membranes,  and  this  causes: 

2.  Reflex  effects : 

Coughing. 

Salivation  and  flow  from  respiratory  mucous  mem- 
brane. 
Respiratory  inhibition  and  irregularity. 
Cardiac  effects. 

3.  Disturbances  of  judgment. 

4.  Loss  of  memory  and  self-control. 

5.  Emotional  tendencies. 

6.  Disturbances  of  special  senses  less  acute;  hissing  and 

roaring  sounds. 

7.  Analgesia. 

8.  Vertigo  and  ataxia. 

9.  Quickened  pulse  and  rise  of  blood-pressure,  probably 

asphyxial. 

10.  Increased  respiration. 

11.  Dilated  pupils. 

^  As  arranged  by  Dixon :    Manual  of  Pharmacology. 


ACTION  OF   THE  ALCOHOL  CHLORAL  GROUP  125 

II.  Xarcotic  Stuge  and  Uncunsciousness: 

1.  Coughing,  retching,  vomiting. 

2.  Delirium,  muttering  to  shouting. 

3.  Tonic  and  clonic  muscular  spasms. 

4.  Reflexes  diminished  but  still  present. 

5.  I  nconsciousness. 

(i.  Respiration  irregular  from  struggling. 
7.  Pulse  accelerated  and  pupil  dilated,  both  from  excite- 
ment. 

III.  Surgical  Anesthesia: 

1.  Muscular  relaxation. 

2.  Loss  of  reflexes. 

3.  Breathing  slower  and  regular  snoring. 

4.  Decrease  in  respiratory  exchange. 

5.  Fall  of  blood-pressure  and  temperature. 

Dilatation  of  skin  vessels. 
Lessened  movements. 
Heat  center  uncontrolled. 

6.  Smaller  pupil  does  not  react  to  light. 

IV.  Stage  Leading  to  Bulbar  Paralysis — Toxic  Stage: 

1.  Loss  of  bladder  and  rectal  reflexes. 

2.  Paralysis  of  vasomotor  center;  fall  of  blood-pressure. 

3.  Paralysis  of  respiration  center. 

4.  Pupils  dilated. 

5.  Depression  or  paralysis  of  cardiac  muscle. 

The  action  of  alcohol,  ether,  chloroform  and  chloral  differs 
mainly  in  the  degree  of  action.  In  working  with  one  of  these,  it  is 
well,  to  compare  the  results  of  all. 

The  chief  actions  are  exerted  on  or  manifested  by: 

1.  The  central  nervous  system. 

2.  Respiration. 

3.  Heart. 

4.  Muscular  work. 

5.  Reflex  time. 
().  Eye. 

7,  Local  action. 

8.  Cieneral  protoplasmic  action. 

The  uses  of  alcohol  in  medicine  aside  from  solvent  and  preserva- 
tive purposes  are: 

1.  Its  local  and  irritant  action. 

2.  Its  action  on  the  central  nervous  system. 

3.  Its  value  as  a  food. 


126     PHARMACOLOGY  OF  HEART  AND  BLOOD-PRESSURE 

Ether,  chloroform  and  chloral  are  not  oxidized  in  the  body,  hence 
their  use  in  medicine  depends  on  the  jBrst  two  properties.  (Cf. 
Alcohol.)  Study  the  absorption,  local  action,  fate  and  excretion  of 
these  drugs. 

In  the  action  of  all  drugs,  part  of  the  action  is  objective,  part 
subjective.  In  animal  experimentation  it  is  apparent  that  the 
objective  side  of  the  action  is  emphasized. 

The  above  table,  slightly  modified  from  Dixon,  gives  the 
symptoms  of  ether  and  chloroform  anesthesia.  Note  the  symptoms 
and  the  stages  carefully,  and  study  especially  the  explanations  of 
these  symptoms. 

Experiment  I. — Action  of  Alcohol  on  a  Normal  Dog. — Before 
administering  a  drug,  always  note  the  weight,  sex,  appearance, 
heart-rate,  character  of  pulse,  eye,  size  of  pupil  and  reflexes,  condi- 
tion of  muscles,  temperature,  etc.,  as  outlined  on  sheet. 

With  a  stomach  tube  introduce  5  c.c.  per  kilogram  of  body  weight 
of  50  per  cent,  alcohol.  Make  complete  observations  and  records. 
Repeat  observations  and  records  every  ten  minutes  for  one  hour. 
At  the  end  of  this  time  anesthetize  the  animal  with  ether  or  chloro- 
form. Note  the  symptoms  closely  and  compare  the  symptoms  of 
anesthesia  in  an  animal  drunk  with  alcohol,  with  the  symptoms 
produced  in  the  anesthetization  of  a  normal  dog. 

Experiment  II. — In  a  second  animal,  for  comparison  with  the  first, 
make  complete  observations  and  records.  Then  give  the  animal 
1  c.c.  of  50  per  cent,  alcohol  per  kilogram  of  body  weight.  Note 
and  record  symptoms  every  two  to  five  minutes.  Compare  with 
dog  1  and  explain  difi^erences. 

Experiment  III. — Ether  Anesthesia. — 1.  Make  and  record  com- 
plete observations,  hold  the  animal  in  the  usual  way  or  tie  him 
securely  on  an  operating  board  quietly  and  gently  so  that  no  pain 
or  excitement  is  caused. 

2.  Record  observations  again. 

3.  Place  an  etherizing  cone  in  the  usual  way  over  the  nose  of  the 
animal  and  drop  ether  on  the  cone  at  the  rate  of  about  10  drops  per 
second.  Continue  this  rate  until  the  animal  is  completely  anes- 
thetized. Make  complete  observations  and  records  every  two 
minutes.  See  whether  or  not  you  can  distinguish  the  stages  of 
anesthesia  as  outlined  by  Dixon.  If  any  of  the  symptoms  cannot 
be  observed,  discuss  and  explain  as  far  as  possible.  , 

Compare  the  action  of  ether  with  the  action  of  alcohol. 
When  the  surgical  anesthesia  is  complete,  remove  the  ether  and 
allow  the  animal  to  come  out  partially.    When  he  reaches  the  excite- 


ACTION  OF  THE  ALCOHOL  CHLORAL  GROUP  127 

ment  stage,  again  administer  the  ether  as  before.  Continue  to 
administer  the  anesthetic  gradually,  increasing  the  rate  if  necessary 
until  the  animal  reaches  the  fourth  stage  and  respiration  is  about 
five  per  minute.  Make  complete  observations  and  records  at  this 
time.  Remove  the  cone  and  untie  the  animal  and  allow  him  to 
recover,  making  complete  records  every  five  minutes  during  this 
period.    After  twenty-four  hours  make  another  set  of  records. 

Compare  the  symptoms  of  ether  anesthesia  with  alcoholic  intoxi- 
cation. 

Experiment  IV. — Repeat  Experiment  III,  using  chloroform  instead 
of  ether. 

Experiment  V. — Effect  of  Alcohol  on  Frogs. — 1.  With  a  hypo- 
dermic syringe  inject  into  the  anterior  lymph  sac  of  a  frog  2  c.c.  of 
50  per  cent,  alcohol.  Place  the  animal  under  a  battery  jar  or  wire 
basket  on  a  piece  of  moist  cotton  and  make  observations  on  the 
reflexes  and  pupils  every  five  minutes  for  thirty  minutes  (Fig.  25.) 

2.  On  a  second  frog  repeat  observations  using  1  c.c.  of  alcohol. 
Place  the  animal  in  a  cylinder  filled  with  water  and  inverted  in  a 
vessel  of  water  so  that  the  cylinder  contains  no  air.  Compare  and 
explain  the  behavior  of  this  animal  with  that  of  a  normal  frog. 

3.  On  a  third  animal  use  0.5  c.c.  alcohol.  Note  the  condition  of 
the  reflexes  and  the  size  of  the  pupil. 

After  the  observations  are  complete,  place  the  animals  in  a  tank 
and  observe  at  the  end  of  twenty-four  hours. 

Experiment  VI. — Effect  of  Alcohol  on  Reflex  Time. — Reaction 
Time. — Instruments  needed;  a  kymograph,  a  muscle  lever,  a  signal 
magnet,  probe  and  scissors. 

Method: 

1 .  Pith  brain  and  medulla  of  frog.  Wait  fifteen  to  twenty  minutes 
to  allow  recovery  from  shock. 

2.  Adjust  kymograph  to  run  about  2  cm.  per  second. 

3.  Attach  muscle  lever  and  signal  magnet  about  3  cm.  below  it. 

4.  Insert  electrodes  from  the  secondary  coil  into  the  skin  of  the 
frog;  adjust  induction  coil  so  as  to  produce  minimal  stimulus,  given 
a  crossed  reflex  in  about  two  seconds. 

5.  Proceed  to  obtain  crossed  reflex  time,  taking  average  about 
of  five. 

(a)  Normal. 

(6)  0.5  c.c.  of  20  per  cent,  alcohol  into  dorsal  lymph  sac. 

(c)  After  five  to  ten  minutes'  rest  repeat  (b)  and  4. 

(d)  After  thirty  minutes'  rest  repeat  (h)  "     " 

(e)  After  sixty  minutes'  rest  repeat  (b)  "     " 


128      PHARMACOLOGY  OF  HEART  AND  BLOOD-PRESSURE 

N.  B. — Differentiate  between  direct  response  to  stimulus  and 
crossed  reflex  when  both  appear. 

Take  tracings  below  one  another. 

Between  each  tracing  rest  about  two  minutes,  to  avoid  fatigue. 

In  a  second  frog  prepared  in  the  same  way,  test  the  reflex  time 
obtained  by  dipping  the  toe  into  0.5  per  cent.  HCl  or  acetic  acid. 
Dip  the  toe  into  the  acid,  the  same  amount  each  time,  and  note  the 
time  taken  to  withdraw  the  toe.  The  time  can  most  conveniently 
be  measured  by  a  stop  watch. 

Conclusion. — ^Record  your  results  in  table  form. 

Questions. — 1.  On  what  side  of  the  reflex  arc  do  these  drugs  act? 

2.  In  what  way  may  drugs  effect  response? 

3.  What  is  the  significance  of  your  results  as  applied  to  every- 
day life? 

4.  Explain  the  coughing  under  ether,  the  vertigo,  salivation, 
dilated  pupils,  loss  of  reflexes,  etc.,  throughout  the  four  stages. 

Experiment  VII. — Effect  of  Alcohol  on  the  Heart  of  a  Frog. — 1. 
Pith  a  frog  both  brain  and  cord.  Expose  the  heart.  Attach  a 
writing  lever  to  the  heart  by  the  suspension  method. 

2.  Take  a  normal  heart  tracing.  (Drum  moving  1  cm.  in  ten 
seconds.) 

3.  Drop  5  per  cent,  alcohol  on  the  heart  in  a  steady  stream  and 
continue  the  tracing.    If  there  is  no  action  use  10  per  cent,  alcohol. 

4.  When  the  action  is  very  pronounced,  irrigate  the  heart  with 
Ringer's  solution. 

5.  On  the  same  animal  repeat  experiment,  using  a  saturated 
solution  of  ether  in  Ringer's  solution. 

6.  On  the  same  animal  repeat  experiment,  using  a  saturated  solu- 
tion of  chloroform  in  Ringer's  solution. 

7.  Add  a  solution  of  1  to  1000  adrenalin  to  the  heart  when  it  is 
almost  stopped. 

8.  Tabulate  your  results. 

Normal  heart: 

(a)  Rate. 

(b)  Amplitude. 
Alcoholized  heart: 

(a)  Rate. 

(b)  Amplitude. 

9.  From  your  experiment,  can  alcohol  be  used  as  a  heart  stimu- 
lant? If  the  results  are  not  definite  use  weaker  or  stronger  solutions 
of  the  alcohol. 


EFFECT  OF  GENERAL  ANESTHETICS  ON  CIRCULATION     129 


THE  EFFECT  OF  GENERAL  ANESTHETICS  ON  THE  CIRCULA- 
TION, RESPIRATION  AND  TEMPERATURE. 

Outline  of  study  of  drugs  on  heart : 

I.  Heart  Rate,  influence  of  drugs  on,  chronotropic  influence; 
irritability  of  the  muscle  tissue,  bathmotropic  influence;  conduc- 
tivity of  the  tissue,  dromotropic;  force  and  energy  of  contractions; 
inotropic  influence  manifested  by  the  blood-pressure  and  the  pulse- 
pressure. 

II.  Vessels:  Constriction;    dilations. 

Record  weight,  character  and  rate  of  respiration  and  heart  beat, 
rectal  temperature,  and  general  appearance  of  the  dog  or  rabbit. 

1.  Induce  surgical  anesthesia  with  ether.  Insert  tracheal  cannula 
and  the  cannula  for  the  blood-pressure.  Insert  cannula  in  the 
femoral  vein  for  injections.  Record  respiration  and  blood-pressure 
on  a  drum  moving  about  2  cm.  in  ten  seconds.  Get  complete  records 
for  a  period  of  ten  minutes.  Push  the  anesthetic  gradually  until  the 
animal  breathes  about  ten  times  per  minute.  Note  carefully  blood- 
pressure  and  the  condition  of  the  heart  at  this  time  and  compare 
the  influence  of  other  anesthetics  on  the  heart  and  blood-pressure 
when  the  respiration  is  slowed  to  the  extent  that  it  is  in  this  case. 

2.  Remove  the  ether  and  connect  the  tracheal  cannula  with  the 
nitrous  oxide  apparatus.  Adjust  this  so  that  the  mixture  of  nitrous 
oxide  and  air  will  produce  anesthesia.  Take  records  and  continue 
for  ten  minutes.  Remove  the  apparatus  and  take  records  as  the 
animal  is  coming  out.  When  this  occurs,  administer  ether  again 
until  the  blood-pressure  and  the  respiration  is  constant. 

.3.  Replace  the  ether  by  ethyl  chloride.  This  can  be  done  by 
spraying  the  ethyl  chloride  into  a  bottle  connected  with  the  tracheal 
cannula.  Continue  the  ethyl  chloride  for  ten  minutes  and  take  a 
complete  set  of  tracings.  Allow  the  animal  to  come  out;  take 
tracings  during  the  recovery.  Compare  the  time  of  recovery  from 
ethyl  chloride  and  nitrous  oxide. 

4.  Administer  ether  again  and  push  it  gradually  until  the  animal 
breathes  about  ten  times  per  minute.  Take  tracings  and  records 
at  this  time.  Allow  the  animal  to  come  out;  take  records  as 
before.  Again  administer  ether  until  the  respiration  and  blood- 
pressure  are  constant. 

F).  Give  chloroform  by  the  drop  method  (see  Fig.  2),  increasing 
gradually  until  the  animal  breathes  about  ten  times  per  mimite. 
Allow  the  animal  to  recover,  an<l  take  tracings  during  the  recovery. 
9 


130     PHARMACOLOGY  OF  HEART  AND  BLOOD-PRESSURE 

Then  give  chloroform  again  gradually  until  heart  or  respiration 
stops.  Take  tracing  and  when  pulse  is  imperceptible  open  the 
animal  and  examine  the  condition  of  the  heart. 

Compare  your  results  and  give  opinion  of  the  relative  influence 
of  the  drugs  studied  on  the  heart  and  respiration.  How  do  your 
results  compare  with  the  report  of  the  Hyderabad  Commission? 

The  Direct  and  Reflex  Effect  of  Ether  and  Chloroform  on  the  Heart. 
— Different  sections  should  compare  the  results  of  the  following 
experiments.     Take  complete  record  of  animals. 

Experiment  I. — Anesthetize  a  dog  with  ether.  Prepare  for  blood- 
pressure  and  respiration  tracings.  After  tracings  have  been  taken, 
gradually  push  the  ether  until  the  animal  dies.  Which  stops  first, 
heart  or  respiration? 

Experiment  n. — Repeat  (I),  but  use  chloroform  after  the  records 
are  commenced. 

Experiment  HI. — Anesthetize  with  ether  as  before  and  commence 
records  of  heart  and  respiration.  When  records  are  satisfactory, 
allow  animal  to  come  out,  then  administer  ether  quickly,  pushing 
it  until  the  animal  dies.  Which  stops  first,  heart  or  respiration? 
Perform  autopsy  at  once  and  examine  heart. 

Experiment  IV. — Repeat  IH,  using  chloroform  instead  of  ether. 

Experiment  V. — Repeat  HI,  but  before  using  the  ether,  inject  intra- 
venously 2  c.c.  of  1  per  cent,  atropin.  Isolate  and  stimulate  the 
vagus.  After  a  few  minutes  stimulate  the  vagus  again.  When  stimu- 
lation of  the  vagus  has  no  influence  on  the  heart,  administer  ether 
rapidly  until  the  animal  dies.  Which  stops  first,  respiration  or  heart? 

Experiment  VI.^ — Repeat  V,  but  use  chloroform  instead  of  ether. 

Experiment  VH. — Anesthetize  an  animal  with  ether.  Take  rate 
of  heart  and  respiration.  Thoroughly  cocainize  the  nose  and  throat 
by  washing  or  swabbing  the  membranes  with  5  per  cent,  cocain. 
Allow  the  animal  to  recover  from  the  anesthetic  and  repeat  the 
anesthetization.  Does  the  removal  of  the  irritation  of  the  nasal 
mucous  membranes  influence  the  action  of  the  drug  on  the  heart? 

Compare  results  of  this  series  of  experiments  with  the  report  of 
the  Hyderabad  Commission. 

What  factors  are  operative  in  stoppage  of  the  heart  under  anes- 
thesia? 

How  would  you  prove  that  reflexes  play  a  part? 

Questions  regarding  the  action  of  alcohol  on  the  central  nervous 
system: 

1.  What  is  the^main  action  of  the  alcohol  group  of  drugs  on  the 
central  nervous  system? 


EFFECT  OF  GENERAL  ANESTHETICS  ON  CIRCULATION     131 

2.  Compare  the  action  of  the  alcohol  group— methane  group— and 
the  aromatic  series  on  the  central  nervous  system. 

3.  How  would  you  prove  that  a  drug  stimulates  the  psychic 
functions,  motor  functions  and  sensory  functions  of  the  central 
nervous  system? 

4.  Compare  the  action  of  alcohol,  atropin,  strychnin,  picrotoxin 
caffein,  digitalis  and  morphin  on  the  central  nervous  system. 

5.  ^Yhat  is  the  fate  of  alcohol,  ether,  chloroform,  benzene,  benzine 
and  strychnin  in  the  body? 

6.  What  is  the  proof  that  a  drug  stimulates  the  motor  areas? 
How  do  you  explain  the  increase  in  motion  in  some  phases  of  alco- 
holic intoxication?  Compare  and  explain  the  action  of  alcohol, 
cocain  and  atropin  on  these  functions. 

7.  Differentiate  alcohol  intoxication,  morphin  poisoning  and 
cerebral  hemorrhage. 

8.  Compare  and  explain  the  action  of  alcohol,  chloral,  morphin 
and  the  eserin  pilocarpin  group  of  drugs  on  the  eye.  What  drugs 
acting  centrally  contract  or  dilate  the  pupil? 


CHAPTER  VIII. 
THE  CLOSED  METHOD  OF  ANESTHESIA. 

The  closed  method  of  anesthesia  has  been  developed  by  Jackson.^ 
The  method  consists  essentially  in  having  the  animal  breathe  from 
a  closed  vessel  containing  a  small  amount  of  air.  The  exhaled  CO2 
is  absorbed  by  a  solution  of  NaOH  placed  in  the  bottom  of  the 
vessel.  The  oxygen  supply  is  furnished  from  an  oxygen  tank  and 
the  stream  of  oxygen  is  just  sufficient  to  supply  the  needs  of  the 
animal.  It  is  blown  through  the  NaOH  and  in  this  way  keeps  this 
solution  stirred  up  so  that  it  will  absorb  more  CO2. 

The  advantage  of  the  method  is  that  less  ether  is  required,  but 
whether  or  not  it  will  supercede  the  older  methods  is  yet  to  be 
decided. 

NITROUS  OXIDE  ANESTHESIA  ON  THE  DOG. 

A  short  conical  glass,  like  a  short  percolater,  may  be  used  as  an 
inhaler,  and  can  be  made  to  fit  the  animal's  head  by  means  of  gauze. 
It  need  not  be  air-tight.  Turn  on  the  gas  and  keep  the  bag  moder- 
ately filled  until  anesthesia  is  induced.  Dogs  are  rather  resistant 
to  nitrous  oxide.  As  soon  as  anesthesia  is  complete,  take  observa- 
tions as  under  ether.  Allow  the  animal  to  come  out  and  compare 
the  return  to  consciousness  with  that  from  ether  and  chloroform. 

The  animal  may  again  be  anesthetized  with  gas  and  ether  started 
while  the  animal  is  still  under  the  influence  of  the  nitrous  oxide. 
Compare  the  animal  anesthetized  with  ether  in  this  way  with  one 
that  was  commenced  with  ether. 

NITROUS  OXIDE  ON  FROGS. 

Demonstration. — 1.  Place  a  frog  in  a  large-mouthed  bottle  or  other 
suitable  vessel  and  insert  a  two-holed  stopper,  with  glass  tubes 
inserted,  for  administration  of  gas  and  exit.  Protect  the  animal 
from  the  direct  force  of  the  gas.  Sufficient  NaOH  should  be 
exposed  in  the  bottle  to  absorb  CO2.  It  should  not  come  in  contact 
with  the  animals. 

1  Journal  of  Laboratory  and  Clinical  Medicine,  1916,  ii,  94  and  145. 


BROMIDES  133 

2.  Allow  the  animal  to  recover  and  note  the  time. 

3.  Anesthetize  again  and  instead  of  allowing  the  animal  to  come 
out  normally,  administer  oxygen. 

4.  Try  the  influence  of  oxygen  alone  on  a  normal  frog. 

5.  Remove  the  frog  and  repeat  experiment  with  a  guinea-pig  or 
mouse. 

6.  Compare  the  action  of  nitrous  oxide  on  the  warm-  and  cold- 
blooded animals  by  placing  them  both  in  the  bottle  together. 
Notice  the  difference  in  the  rapidity  of  anesthesia  and  the  rate  of 
recovery. 

If  it  is  desired  to  know  the  effect  of  pressure  on  these  animals 
a  manometer  may  be  attached. 

THE  SPECIFIC  ACTION  OF  NITROUS  OXIDE. 

If  carbon  dioxide  is  available  its  action  should  be  compared  with 
nitrous  oxide.  It  was  formerly  thought  that  the  entire  action  of 
N2O  was  due  to  asphyxia.  Paul  Bert  proved  that  X2O  has  a  specific 
action.  He  mixed  80  parts  of  N2O  and  20  parts  of  oxygen,  com- 
pressed the  mixtures  Ij  atmospheres  and  found  that  in  this  way 
nitrous  oxide  would  produce  and  continue  anesthesia  indefinitely. 
Eighty  per  cent,  of  nitrous  oxide  and  20  per  cent,  of  oxygen  com- 
pressed Ij  times  gives  eighty  volumes,  the  same  volume  as  the 
original  X2O.  While  the  animal  is  inhaling  the  X2O  it  gets  as  much 
oxygen  as  there  is  normally  in  the  air.  The  resulting  anesthesia, 
therefore,  cannot  be  due  to  asphyxia. 

This  experiment  may  be  more  easily,  if  less  accurately,  carried 
out  by  a  nitrous-oxide  machine  by  setting  it  to  deliver  80  parts  of 
nitrous  oxide  and  20  parts  of  oxygen.  If  this  gas  is  administered 
to  an  animal  in  a  vessel  provided  with  an  outlet  there  is  no  need 
of  the  XaOH  to  absorb  the  CO2. 

BROMIDES. 

General  Actions. — 1.  A  specific  depressing  effect  on  the  nerve 
cells  of  the  central  nervous  system,  motor  and  sensory. 

2.  A  salt  action  in  greater  concentrations. 

3.  During  the  elimination  of  the  drug  by  the  skin,  an  irritant 
action  with  eruptions  may  ensue.  This  is  especially  prominent  on 
the  head  and  shoulders. 

4.  In  prolonged  use  or  after  large  doses  there  is  an  irritant  action 
of  the  stomach,  with  nausea  and  vomiting. 


134  THE  CLOSED  METHOD  OF  ANESTHESIA 

5.  The  collective  untoward  symptoms  are  known  as  "bromism." 
Most  prominent  are  nausea,  vomiting,  skin  eruption,  pigmentation 
of  the  skin,  sleepiness,  mental  dulness,  muscular  weakness  and 
unsteady  gait.  Compare  the  action  of  alcohol,  morphin,  bromides 
and  cannabis  on  the  heart,  respiration,  central  nervous  system, 
digestive  tract,  eye  and  kidney. 

Experiments  or  Demonstrations. — In  a  series  of  cats  or  rabbits, 
treat  the  individuals  as  follows: 

1.  Give  3  grams  per  kilo  body  weight  of  sodium  or  potassium 
bromide  in  solution  by  stomach-tube  and  note  the  effect. 

2.  Give  the  same  amount  of  bromide  as  in  1.  Repeat  in  two  hours 
if  there  are  no  symptoms.  An  hour  after  the  second  dose  give  10  c.c. 
of  20  per  cent,  camphor  in  oil  per  kilo  of  body  weight  by  stomach- 
tube. 

3.  Give  this  animal  10  c.c.  of  20  per  cent,  camphor  in  oil  per  kilo 
of  body  weight,  and  note  the  results  for  two  hours.  What  is  the 
action  of  the  bromide  in  controlling  epileptoid  convulsions  produced 
by  camphor? 

4.  Dissolve  0.5  gm.  of  sodium  or  potassium  bromide  in  100  c.c. 
of  water.  Add  chlorin  water  and  shake  in  a  separatory  funnel  with 
25  c.c.  of  chloroform.  A  yellow  to  orange  color  should  be  imparted 
to  the  chloroform.    Compare  this  color  with  the  following  test: 

5.  Collect  a  sample  of  urine  and  make  a  test  as  in  4. 

6.  Take  1  gm.  of  potassium  or  sodium  bromide  dissolved  in  100 
c.c.  of  water.  In  two  hours  collect  the  urine  and  apply  the  test  as 
in  4. 

CANNABIS. 

Cannabis  is  so  unreliable  in  its  action  that  little  satisfactory  work 
can  be  done  with  it  in  the  laboratory.  It  is,  however,  one  of  the 
biological  standardized  drugs  of  the  Pharmacopoeia.  The  method 
which  is  crude  at  best,  consists  in  administering  the  drug  to  dogs 
in  the  form  of  a  capsule,  0.004  gram  of  the  extract  of  0.03  c.c.  of 
the  fluidextract  or  0.3  c.c.  of  the  tincture  per  kilo  of  body  weight; 
this  should  produce  symptoms  of  incoordination. 

Experiment  I. — ^Weigh  a  dog  and  prepare  a  capsule  containing 
0.004  gram  per  kilo  body  weight  of  the  extract  of  cannabis.  Hold 
the  animal's  head  back,  withdraw  the  tongue  and  place  the  capsule 
back  as  far  as  possible.  Release  the  tongue  and  hold  his  mouth 
shut;  slap  the  throat  lightly,  if  necessary,  to  make  the  animal 
swallow.    Watch  the  animal  for  two  or  three  hours. 


CANNABIS 


135 


Experiment  II. — A  corresponding  amount  of  the  tincture  may  be 
administered  in  capsule  or  the  sokition  may  be  dropped  on  the  back 
of  the  tongue  from  a  pipette.  If  this  can  be  done  satisfactorily 
it  is  better  than  using  the  capsule,  as  all  uncertainty  of  solution  is 
avoided.    Compare  this  action  with  morphin  and  the  bromides. 

Experiment  III. — Groups  of  students  should  take  the  following 
doses  of  cannabis  one  hour  before  the  evening  meal  and  report 
the  effects  next  day: 

Group      I.  1.0  c.c.  of  the  tincture. 
II.  1.5  c.c.  "     " 

III.  2.0  c.c.  "    " 

IV.  3.0  c.c.  "     " 

Assay  of  Cannabis. — The  assay  is  based  on  the  fact  that  this 
drug  produces  certain  symptoms  of  muscular  incoordination.  The 
method  consists  in  ascertaining  the  dose  of  the  drug  to  be  tested 
that  will  produce  these  symptoms  of  incoordination  in  a  dog  and 
then  adjusting  its  strength  by  comparison  with  a  standard  prepara- 
tion. 


Fig.  31. — Techiiic  of  adniiui.stering  capsules  to  dog  by  mouth. 


Dog.<f. — Since  the  animals  differ  greatly  in  susceptibility  a  number 
of  animals  should  be  tried.  As  a  rule,  fox  terriers  serve  well,  but 
any  species  may  do.  Two  dogs  should  be  provided  for  each  assay. 
The  animals  should  be  at  least  one  year  old,  healthy  and  kept  under 
the  best  .sanitary  conditions.    If  used  for  more  than  one  test,  three 


136  THE  CLOSED  METHOD  OF  ANESTHESIA 

days  should  elapse  between  tests.  The  tests  should  be  made  In  a 
quiet  room  and  free  from  excitement,  and  the  animals  should  not 
see  each  other. 

Preparation  of  the  Drug. — The  fluidextract  may  be  given  in  soft 
capsules,  or  the  extract  made  into  soft  pills  may  be  used.  The  stan- 
dard preparation  and  the  drug  to  be  tested  should  both  be  prepared 
in  the  same  form.  The  animal  should  be  starved  for  twenty-four 
hours  in  order  to  hasten  absorption.  The  drug  is  easily  adminis- 
tered by  placing  on  the  back  of  the  tongue  (Fig.  31).  Water  may 
be  given  to  aid  swallowing  if  thought  advisable. 

The  average  dose  of  the  standard  preparation  is  given  to  one  dog 
and  a  like  dose  given  to  the  other  of  the  solution  to  be  tested.  After 
one  hour  both  dogs  should  be  examined  for  symptoms  of  muscular 
incoordination.  This  in  most  animals  consists  of  a  slight  swaying 
movement  when  the  animal  stands  and  some  ataxia  when  it 
moves  about.  Observation  should  be  made  frequently  during  the 
second  hour  after  the  administration  of  the  drug.  The  results 
obtained  from  the  first  test  should  be  confirmed  at  an  interval  of 
not  less  than  three  days  by  repeating  the  administration,  but  in  the 
reverse  order,  i.  e.,  the  standard  preparation  should  be  given  to 
the  dog  which  received  the  drug  to  be  assayed  in  the  first  trial. 

In  subsequent  tests  the  doses  may  be  modified  so  that  similar 
symptoms  are  produced  by  each  sample  of  drug.  If  the  preparation 
to  be  tested  is  below  standard  its  dose  may  be  increased,  or  if  above 
strength  its  dose  may  be  lessened  until  the  equivalent  doses  of  each 
is  found.  The  same  dogs  may  be  used  over  long  periods  of  time, 
even  for  some  years,  but  occasionally  they  have  to  be  discarded,  as 
in  some  cases  they  seem  to  learn  the  effect  of  the  drug  and  so  refuse 
to  stand  up.    A  certain  degree  of  tolerance  necessitates  larger  doses. 

Standard. — ^There  is  no  definite  chemical  that  can  be  adopted  as 
a  standard.  A  carefully  prepared  and  preserved  extract  or  fluid- 
extract  may  be  used.  A  standard  fluidextract  will  produce  inco- 
ordination in  dogs  when  administered  in  the  dose  of  0.03  c.c.  per 
kilogram  of  body  weight  of  the  dog.  0.004-gram  doses  of  the 
extract  administered  in  the  same  way  or  0.03  c.c.  of  the  tincture  per 
kilo  body  weight  will  produce  similar  symptoms. 


CHAPTER  IX. 

ACTION  OF  STRYCHNIN,  PICROTOXIN  AND  CURARA 
ON  THE  CENTRAL  NERVOUS  SYSTEM. 

Study  the  action  of  these  drugs  on  the  nervous  system,  and 
especially  changes  in  irritabiUty  and  determine  the  site  of  action: 
Technic. — Take  four  frogs  and  number  them  from  1  to  4.' 
Experiment  I. — Note  the  general  condition,  normal  movements 
and  response  to  stimuli.  With  a  glass  rod,  pencil  or  similar  instru- 
ment, determine  the  slightest  stimulus  that  will  make  the  animal 
move  or  jump.  Note  the  position  of  the  animals  before,  during 
and  after  such  movement.  Keep  this  in  mind  so  that  any  change 
after  the  administration  of  the  drug  may  be  noted. 

(a)  Into  the  ventral  lymph  sac  of  animal  No.  1  inject  0.5  c.c.  of 
0.01  per  cent,  strychnin  sulphate  solution. 

(b)  Into  No.  2  inject  in  the  same  manner  1  c.c.  of  0.01  per 
cent,  strychnin  sulphate  solution. 

(c)  Into  the  lymph  sac  of  No.  3  inject  0.3  c.c.  of  1  per  cent, 
strychnin  sulphate  solution.  Keep  the  time  of  injections  and  note 
the  onset  of  change  in  irritability,  tetanus  and  paralysis.  Note 
especially  the  type  of  spasm  and  compare  with 

(d)  No.  4,  into  which  you  have  injected  1  c.c.  of  0.04  per  cent, 
picrotoxin  solution.  Compare  the  positions  which  the  legs  of  the 
animals  assume.  Note  the  tendencies  to  opisthotonos,  emprostho- 
tonos  and  pleurothotonos. 

Experiment  n. — When  satisfied  with  observations,  determine  the 
seat  of  action  of  the  drugs  as  follows:  Anesthetize  one  of  the 
strychnin  animals  which  shows  strong  convulsions  and  the  picro- 
toxin animal  with  ether  by  placing  them  under  a  jar  together  with 
a  piece  of  cotton  soaked  in  ether  (see  Eig.  2()).  Note  the  influence 
of  ether  on  the  spasms.  When  anesthetized,  dissect  and  lay  bare 
the  brain  and  medulla.  Isolate  also  one  of  the  sciatic  nerves.  Wait 
for  the  return  of  tetanus.  When  spasms  reappear  cut  the  sciatic, 
which  is  isolated.  If  the  spasms  stop  in  that  leg,  where  is  the 
jjr(;bable  seat  of  action?  Remove  cerebrum  and  optic  nerves  and 
wait  for  the  return  of  the  tetanus.  Now  remove  the  cerebellum 
and  rncdiilJa  and  again  wait  about  fifteen  minutes.    Is  there  any 


138     ACTION  OF  STRYCHNIN,   PICROTOXIN  AND  CURARA 

difFerence  in  the  strychnin  and  picrotoxin  animals?  Finally  pith 
the  cord  with  a  strong  wire  or  pithing  needle.    What  is  the  result? 

Experiment  III. —  To  Determine  the  Relation  of  Sensory  Stimuli  to  the 
Production  of  Convulsions.— Youhson's  experiment:^  Take  one  of 
the  frogs  already  in  tetanus  and  immerse  it  for  a  few  seconds  in  a 
1  per  cent,  solution  of  cocain  hydrochloride  or  in  a  saturated  aqueous 
solution  of  chloretone,  or  paint  the  entire  skin  of  the  animal  with  5 
per  cent,  solution  of  cocain,  using  a  camel's-hair  brush.  Put  the 
animal  in  a  quiet  place,  under  a  bell-jar,  and  in  five  minutes,  if  con- 
vulsions are  still  present,  immerse  a  second  time.  Place  again  under 
the  jar  and  observe  for  thirty  to  sixty  minutes.  If  sensory  stimulus 
from  without  is  necessary  to  elicit  tetanus,  what  would  you  expect 
in  the  present  case?  If  tetanus  fails  to  develop,  apply  a  stimulus 
to  the  skin  by  brushing  it  lightly;  if  no  result,  tap  the  joints  lightly 
and  note  the  results.  Isolate  the  sciatic  on  one  side  and  stimulate 
lightly. 

Criticise  the  experiment.  What  is  the  effect  of  cocain  on  the 
central  nervous  system?     See  Experiment  VIII. 


Fig.  32. — Bernard's  experiment.  The  ligature  excludes  the  circulation  from  the 
leg  while  the  nerve  endings  are  not  influenced  by  the  drug.  Curara  or  other  drug 
may  be  introduced  into  one  of  the  lymph  sacs. 

Experiment  IV. — Claude  Bernard's  Experiment  (Fig.  32). — Strych" 
nin.- — Destroy  the  brain  of  another  frog  and  protect  one  hind  leg  from 
strychnin  by  means  of  a  ligature,  which  will  cut  off  the  circulation 
without  injuring  the  sciatic  nerve.  Now  inject  0.3  c.c.  of  0.1  per 
cent,  strychnin  sulphate  solution  into  the  ventral  lymph  sac.   When 

1  Arch.  f.  Exp.  Path,  and  Pharm.,  vol.  xxvi,  p.  22. 


TECHNIC  139 

convulsions  come  on,  note  whether  the  non-strychninized  leg  par- 
ticipates in  the  convulsions.  See  whether  a  convulsion  can  be 
initiated  by  stimulating  the  protected  leg.  Compare  the  curarized 
frog,  one  of  whose  legs  has  been  protected.  For  comparison  with 
curara,  see  Curara. 

Experiment  Y.— Action  of  Strychnin  on  Turtle  Heart  Strips.— 
Strychnin  on  ventricular  strips:  Suspend  a  ventricular  strip  in  a 
measured  volume  of  0.8  per  cent,  saline  solution  and  take  a  record 
of  the  beating.  When  it  is  beating  rhythmically  add  5  per  cent, 
solution  of  strychnin  in  saline  0.8  until  the  solution  contains  0.01 
per  cent,  strychnin.  Take  records  of  this  for  five  minutes  and 
keep  adding  strychnin  until  the  strip  is  immersed  in  0.2  per  cent, 
strychnin  sulphate.  What  is  the  direct  action  of  strychnin  on  the 
heart  muscle? 

Experiment  VI. — Action  of  Strychnin  on  Mammals. — Demonstra- 
tion.—Count  the  respiration  or  heart-rate  in  a  rabbit  or  cat.  Give 
a  hypodermic  of  0.2  c.c.  of  1  to  1000  strychnin  sulphate.  Note  the 
t}T)e  of  convulsion.  Control  the  spasm  with  ether.  Knowing  the 
method  of  administration  and  the  action  of  the  drug,  how  would 
you  treat  this  case  of  poisoning?  Would  the  treatment  be  different 
if  the  drug  had  been  given  by  the  stomach?  Kill  the  animal  with 
the  anesthetic. 

Experiment  VII. — Action  on  the  Heart  and  Respiration. — Weigh  the 
animal;  count  normal  heart  and  respu-ation  rate.  Anesthetize  with 
ether  or  chloroform  and  agam  count.  Arrange  for  blood-pressure  and 
respiratory  tracings  and  for  injection  into  the  femoral  vein.  Take 
a  continuous  record  on  a  drum  moving  at  about  1  cm.  in  ten  seconds. 
Inject  1  c.c.  of  0.01  per  cent,  strychnin  sulphate  per  kilo  of  body 
weight.  Note  the  effect.  Repeat  the  injection  every  five  minutes 
until  convulsions  are  elicited.  Note  the  eftect  on  blood-pressure  and 
respiration,  especially  during  the  spasm.  Control  the  spasm  by 
pushing  the  anesthetic.  Finally,  study  the  effect  of  pushing  the 
anesthetic  on  the  heart  and  respiration.  Make  use  of  the  animal 
either  for  studying  the  action  of  corrosive  poisons  and  anesthesia 
or  other  work. 

On  a  series  of  dogs  or  cats  the  action  of  strychnin  when  applied 
locally  to  the  central  nervous  system  may  be  studied  as  follows: 
(a)  The  local  nature  of  the  action  and  (6)  the  action  of  strychnin 
on  the  spread  of  reflexes;  (c)  the  modification  of  the  impulse  on 
passage  through  a  strychninized  area.  These  experiments  may  be 
done  under  ether  or  gas  anesthesia. 

1.  Inject   1   c.c.  of  0.2   per  cent,   strychnin   sulphate    into  the 


140     ACTION  OF  STRYCHNIN,  PICROTOXIN  AND  CURARA 

region  of  the  fourth  ventricle  after  withdrawal  of  an  equal  amount 
of  cerebrospinal  fluid.  Do  not  keep  the  animal  under  the  anesthetic 
longer  than  necessary.  Note  the  sensitivity  of  the  head  and  nose 
while  the  tail  end  of  the  animal  is  normal.  Study  the  spread  of 
impulses  from  the  head  caudalward  and  from  below  upward, 

2.  Inject  a  second  animal  with  2  or  3  mg.  in  the  lumbar  region. 

3.  Inject  a  third  animal  in  the  dorsal  region.  Notice  that  the 
region  innervated  from  the  strychnin  part  remains  for  a  long  time 
the  long  part  in  which  the  sensitivity  is  changed.  Note  also  that 
impulses  pass  more  readily  caudalward  than  in  the  reverse  direc- 
tion and  that  impulses  are  not  changed  on  passage  through  the 
strychninized  part. 

Compare  your  results  with  those  of  Houghton,  Muirhead  and 
Baglioni. 

Experiment  VIII. — Synergism  of  Strychnin  and  Cocain. — ^Take 
four  frogs  of  the  same  size.  Into  the  anterior  lymph  sac  of  one 
and  two  inject  2  c.c.  0.1  per  cent,  cocain  hydrochloride.  After 
thirty  minutes  inject  all  with  1  c.c.  0.1  per  cent,  strychnin  sul- 
phate. In  which  do  the  spasms  first  appear?  Whether  or  not 
this  is  synergism,  or  addition  reaction  is  not  known. 

Experiment  DC. — Caffein. — Caffein  produces  convulsions  of  the 
strychnin  type;  inject  1  c.c.  of  1  per  cent,  caffein  solution  into  the 
lymph  sac  of  a  frog.  Compare  the  action  with  picrotoxin  and 
strychnin.  How  would  you  determine  that  the  caffein  action  in 
this  case  is  exerted  mainly  on  the  cord?  Some  species  of  frogs  show 
a  typical  effect. 

Demonstration. — Other  Convulsants  on  Mammals. — ^Administer  to 
cat  or  rabbit  by  the  stomach-tube  about  20  c.c.  total  of  20  per 
cent,  solution  of  camphor  in  oil  (see  Fig.  6.)  Convulsions  usually 
take  place  in  about  a  half  hour,  due  largely  to  stimulation  of  the 
medulla.  Note  that  convulsions  tend  to  persist,  yet  recovery 
commonly  takes  place  despite  the  enormous  dose  of  camphor. 

Action  of  Curara  on  the  Central  Nervous  System  of  Mammals. — 
Strychnin  when  applied  directly  to  motor  nerve  endings  has  a 
curara-like  action,  but  this  is  not  usually  seen  because  the  animal 
dies  from  a  central  action  before  the  peripheral  paralysis  is  apparent. 
Similarly,  curara  has  a  strychnin-like  action  on  the  central  nervous 
system,  but  this  is  not  seen  if  the  peripheral  paralysis  has  developed. 

Demonstration. — To  show  the  central  action  of  curara,  inject 
1  c.c.  of  0.5  per  cent,  curara  filtered  in  water  into  the  fourth  ventricle 
and  make  observations  until  spasms  develop.  Note  that  there  is 
no  peripheral  paralysis. 


TECHNIC  141 

In  ciirara  poisoning  the  motor  endings  are  involved  before  other 
parts  of  the  reflex  arc. 

Experiment  X. — Ligate  a  frog's  leg  high  in  the  thigh  with  the 
exception  of  the  nerve.  Carefully  expose  the  sciatic  on  the  other 
side  with  as  little  trauma  as  possible.  Inject  0.5  c.c.  of  0.1  per  cent, 
curara  solution.  Just  as  voluntary  motion  ceases,  stimulate  the  skin 
of  the  poisoned  leg;  the  unpoisoned  one  will  contract.  Stimulate 
the  sciatic  on  the  poisoned  side;  the  poisoned  muscles  will  stop 
contraction  before  the  muscles  on  the  unpoisoned  side.  The 
muscles  of  the  unpoisoned  side  contract  when  the  sensory  fibers 
of  the  poisoned  sciatic  are  stimulated,  owing  to  reflex  stimulation 
through  the  cord.  This  shows  that  the  sensory  side  of  the  arc  is 
not  affected  by  the  poison  while  the  motor  side  is  poisoned. 

Experiment  XI. —  The  Action  of  Strychnin  on  Reaction  Time. — (a) 
Test  the  reaction  time  on  a  frog  by  the  Tiirck  method,  using  0.5 
per  cent.  acid. 

(6)  Test  the  time  also  when  the  stimulus  is  an  electric  current. 

(c)  Give  the  animal  1  c.c.  of  0.01  per  cent,  strychnin  and  wait 
until  spasms  appear  or  until  the  reflexes  show  a  marked  increase. 

(d)  Test  the  reaction  time  again. 

Is  there  any  relation  between  the  sensitivity  of  the  reflexes  and 
reflex  time? 

Experiment  XII. — Action  of  Strychnin  on  the  Ear. — Determine 
accurately  the  distance  at  which  a  student  can  hear  the  ticking  of 
a  watch.  Note  accurately  the  position  of  the  subject  and  the  dis- 
tance of  hearing.  Now  give  him  315  grain  of  strychnin  sulphate  in 
solution  and  in  thirty  minutes  again  determine  the  range  of  hearing. 

Repeat  this  experiment  with  a  student  before  and  after  0.5  grain 
of  chloral  hydrate. 

Experiment  XIII. — Action  of  Strychnin  on  the  Eye.^ — Determine 
the  extent  of  the  field  of  vision  for  several  colors,  especially  blue, 
with  a  perimeter  before  and  after  strychnin.  Give  3V  grain  of  strych- 
nin sulphate  in  solution  and  after  thirty  minutes  again  determine 
the  area  of  the  usual  field.     Compare  before  and  after  strychnin. 

QnedioTi.<i. — 1.  How  does  strychnin  influence  vision? 

2.  Compare  the  actions  of  morphin  and  strychnin  on  the  eye. 

3.  How  does  atropiu,  pilocarpin,  morj)hin,  strychnin,  cocain, 
epinef)hrin  and  silver  salts  dift'er  in  their  actions  on  the  eye? 

4.  Make  a  diagram  of  the  nerves  and  muscles,  intrinsic  and 
extrinsic,  of  the  eye  and  locate  the  points  of  action  of  the  drugs 
acting  on  the  eye. 

'  Note  size  of  tlio  pupil  ui  a  Htudont,  before  and  after  Htrycliiiin, 


142     ACTION  OF  STRYCHNIN,   PICROTOXIN  AND  CURARA 

5.  From  your  experiments,  where  is  the  site  of  the  action  of 
strychnin?     Give  reasons. 

6.  Did  strychnin  in  this  case  produce  any  change  in  spontaneous 
activity? 

7.  What  changes  did  strychnin  produce  in  respiration? 

8.  What  change  did  strychnin  produce  in  the  reflexes  studied? 
Do  the  facts  you  have  noticed  indicate  where  and  how  strychnin 
acts  to  produce  this  effect?    Explain. 

9.  Are  the  convulsions  dependent  upon  afferent  impulses  and  if 
so,  what  is  your  proof? 

10.  Are  the  convulsions  dependent  upon  changes  in  the  peripheral 
tissues,  motor  nerves,  sensory  nerves  or  muscles?     Proof. 

11.  Compare  the  actions  of  strychnin,  atropin,  morphin,  caffein, 
bromides,  cannabis  indica  and  alcohol  on — 

(a)  Central  nervous  system. 
(6)  Heart  and  respiration. 

(c)  Kidneys. 

(d)  Intestine. 

(e)  Skin,  secretion  of  drugs  by,  and  influence  on,  by  drugs. 


CHAPTER  X. 
PARALYSIS  OF  MOTOR  NERVE  ENDINGS. 

Action  of  Drugs  on  Motor   Nerve  Endings  in  Striated  Muscle. 

CURARA. 

Drlgs  that  act  on  nerve-endings  may  cause  either  stimulation 
or  depression.  The  action  of  a  drug  on  nerve-endings  may  be  deter- 
mined by  studying  the  function  of  the  nerve  before  and  after  the 
exhibition  of  the  drug. 

In  pharmacology  the  action  of  curara  is  a  classic  both  because 
of  its  definite  and  easily  analyzed  action  and  also  because  of  its 
value  in  illuminating  the  methods  of  determining  the  action  of  a 
drug.    It  is  not  used  in  medicine. 

Curara  (arrow  poison)  is  an  impure  native  extract  prepared  from 
an  unkno^\'n  species  of  strychnos.  It  varies  so  in  strength  that  the 
dose  cannot  be  accurately  given.  Begin  with  a  small  dose  and 
repeat  every  fifteen  to  thirty  minutes  until  the  action  is  plainly 
obtained. 

Experiment  I. — Action  of  Curara  on  Mammals. — Morphinize  and 
chloroform  a  dog.  Take  the  blood-pressure  and  introduce  a  tracheal 
cannula  to  take  the  respiration  by  the  intratracheal  method. 
Arrange  the  apparatus  to  be  ready  for  artificial  respiration  in  case 
of  need.  Inject  intravenously  5  c.c.  of  1  per  cent,  curara.  AH 
movements  of  voluntary  muscles,  including  the  respiratory  move- 
ments, will  stop  almost  immediately.  The  heart-rate  and  the 
blood-pressure  will  remain  good  and  by  the  application  of  artificial 
respiration  the  circulation  may  be  maintained  for  several  hours. 
If  too  much  of  the  drug  has  not  been  administered  it  will  be  elimi- 
nated and  the  animal  will  recover. 

Experiment  11. —  The  Central  Action  of  Curara. — Curara  given  by 
mouth  lias  no  action.  The  paralyzing  action  is  seen  only  when 
it  is  given  hypodermically  or  intravenously.  Curara  has  also  a 
central  action  like  strychnin.  Ordinarily  this  is  not  seen  because 
of  the  i>cripli('rul  j^aralysis.  If,  however,  curara  is  injected  into  the 
fourth  ventricle  of  a  dog,  spasms  resembling  strychnin  soon  develop. 


144  PARALYSIS  OF  MOTOR  NERVE  ENDINGS 

Demonstration. — Inject  1  c.c.  of  1  per  cent,  curara  into  the  fourth 
ventricle  and  note  the  effect  on  the  animal  for  an  hour  or  longer. 
When  satisfied  as  to  the  central  action,  inject  the  same  amount 
intravenously  and  watch  the  effect.  Repeat  the  intravenous  injec- 
tion if  necessary. 

Experiment  III. — ^To  determine  whether  a  motor"  paralysis  is 
central  or  peripheral,  the  sciatic  nerve  in  a  frog  is  exposed  and 
stimulated  electrically.  If  there  is  no  response  the  paralysis  is 
peripheral.  If  the  muscle  contracts  the  central  seat  of  the  paralysis 
is  located  by  successive  stimulation  of  the  cord  and  medulla  and 
cerebrum,  or  by  ablation  in  the  reverse  direction,  cerebrum,  medulla 
and  cord. 

A  peripheral  paralysis  may  be  in  the  nerve  trunk,  the  endings  or 
the  muscle  fibers.  No  drug  is  known  which  has  a  selective  action 
on  the  motor  nerve  trunk  when  applied  systemically.  The  pos- 
sibility of  this  action  may  be  excluded  by  the  curara  experiments 
described  below.  If  the  motor  endings  are  paralyzed  the  muscle 
will  contract  if  the  electrodes  are  laid  directly  upon  it. 

Claude  Bernard'' s  Experiment. — 1.  Observe  frog  and  note  whether 
or  not  the  reflexes  are  normal. 

2.  Pith  the  brain  and  prevent  as  little  loss  of  blood  as  possible. 
The  better  the  circulation  the  quicker  the  absorption.  Expose  the 
sciatic  on  one  side  in  the  thigh  for  half  an  inch.  Pass  a  strong 
thread  under  the  nerve  and  tie  tightly  around  the  limb,  excluding 
the  nerve.  This  should  stop  the  circulation  in  the  limb.  Inject  into 
one  of  the  lymph  sacs  0.5  c.c.  of  1  per  cent,  curara  in  0.75  per  cent, 
salt  solution.  When  the  paralysis  is  complete,  isolate  both  sciatics 
up  to  the  vertebral  column.  Stimulate  the  anterior  part  of  the 
animal  with  the  electrodes  and  note  results.  Now  lay  both  sciatics 
on  the  electrodes;  stimulate.  The  muscles  of  the  ligatured  limb  will 
contract.  This  proves  that  the  nerve  trunks  are  not  paralyzed. 
Now  stimulate  the  muscles  of  the  poisoned  leg  directly.  This  proves 
whether  the  muscles  are  paralyzed  or  not.  Where,  then,  must  the 
action  of  curara  be  located?  If  the  action  were  on  the  central 
nervous  system  what  would  be  the  results  of  the  above  stimulation  ? 

Experiment  IV. — Action  of  Curara  on  Muscle-nerve  Preparation. — 
Lay  a  slide  across  a  small  evaporating  dish  containing  the  drug  dis- 
solved in  normal  saline;  the  solution  should  not  reach  the  slide. 
Make  two  muscle-nerve  preparations;  preserve  the  entire  length 
of  the  sciatic  nerve  in  a  fresh  frog.  Lay  the  muscle  of  one  prepara- 
tion on  the  slide,  letting  the  nerve  dip  in  the  solution.  Lay  the 
nerve  of  the  other  preparation  on  the  slide,  letting  the  muscle  lie 


CURARA 


145 


in  the  solution.  Stimulation  of  the  immersed  nerve  gives  a  con- 
traction in  (Xo.  2)  as  does  stimulation  of  the  muscle  directly.  This 
proves  the  nerve  fiber  is  not  affected.  Stimulation  of  the  muscle  in 
two  gives  contraction,  therefore  the  muscle  is  not  poisoned.  Stimula- 
tion of  the  nerve  of  two  gives  no  contraction,  therefore  the  muscle  is 
not  affected  nor  is  the  nerve ;  the  toxic  effect  of  the  curara  must  be 
between  the  two  or  on  the  nerve  endings.  Compare  this  action  with 
fatigue.    The  order  of  fatigue  is  nerve-cell,  nerve-ending,  muscle. 

Demonstration. — Drugs  acting  similarly  to  curara  when  injected 
into  the  lymph  sac  of  frogs. 

1.  All  quaternary  ammonium  bases. 

2.  Camphor,  0.1  gram  in  oil  or  saline. 

3.  Lobelin,  0.210  gram. 

4.  Coniin,  0.010  gram. 

5.  Magnesium  sulphate,  1.5  c.c.  of  50  per  cent,  solution. 

6.  Strychnin — paralytic  doses.    This  does  not  kill  frogs  as  rapidly 
as  mammals. 

7.  Methyl  strychnin. 

8.  Amyl  quinin. 

9.  Phosphorus  arsenic  compounds  corresponding  to  the  quater- 
nary ammonium  bases. 


Fio.  33.- 


-Method  of  injection  into  the  femoral  vein.     The  same  method  can  be  used 
to  withdraw  blood  from  the  vein. 


Experiment  V. — Curara  on  Non-anesthetized  Animals. — Inject  1 
c.c.  of  1  per  cent,  curara  into  the  femoral  vein  of  a  dog  (Fig.  33.) 
Observe  closely  the  progress  of  paralysis.  If  this  dose  is  not  suffi- 
cient inject  more.  When  paralysis  of  the  leg  muscles  is  complete 
give  artificial  resi)iration  if  necessary.  The  animal  may  be  saved  in 
this  way.  Physostigmin,  4  to  5  mg.  per  kilo,  has  an  antidotal  effect. 

Stimulation    of    Motor    Nerve    Endings. — Choi  in,  guanadin    and 
pliy.iostigrrnii  stimulate  motor-iuTvc  endings  and  so  facilitate  the 
passage  of  impulses  to  the  muscles. 
10 


146  PARALYSIS  OF  MOTOR  NERVE  ENDINGS 

Experiment  VI. — Inject  a  dog  hypodermically,  or  very  slowly  intra- 
venously, with  1  c.c.  of  1  per  cent,  solution  of  curara  and  observe  the 
animal  for  ten  minutes.  Repeat  the  injection  until  complete  motor 
paralysis  is  apparent.  If  too  much  has  not  been  given  the  animal  will 
recover.  Study  the  symptoms  during  recovery.  In  another  animal 
treated  in  the  same  way,  study  the  effect  of  the  intravenous  injection 
of  1  per  cent,  physostigmin  in  0.5  c.c.  doses. 

Experiment  VII. — Anesthetize  a  dog.  Introduce  a  tracheal  cannula 
and  take  respiratory  tracing.  Take- the  blood-pressure  at  the  same 
time.  Arrange  for  artificial  respiration  when  needed.  Inject  into  the 
femoral  vein  0.5  c.c.  per  cent,  curara  solution.  Repeat  this  occa- 
sionally until  the  respiratory  muscles  are  paralyzed.  When  this 
happens  use  artificial  respiration  intratracheally.  Now  inject  intra- 
venously a  1  per  cent,  solution  of  physostigmin  0.5  c.c.  at  a  time. 
This  will  stimulate  the  nerve-endings.  The  animal  soon  regains 
the  power  of  automatic  respiration. 

If  too  much  curara  has  been  given  the  animal  will  not  recover 
its  power  of  respiration.  Study  the  influence  of  the  drug  on  the 
heart-rate,  blood-pressure  and  respiration.  Observe  especially  the 
time  of  cessation  of  heart  and  respiration.  What  are  the  factors 
involved  in  sustaining  blood-pressure,  and  how  are  these  modified 
by  the  use  of  curara? 

Note. — ^Nearly  any  drug  in  sufficient  concentration  will  effect 
nerve  fibers  if  applied  directly  to  them.  There  is  no  drug  known 
that  shows  a  selective  action  for  nerve  fibers,  and  when  drugs  are 
administered  systemically  they  will  cause  the  death  of  an  animal 
from  an  action  on  some  other  part  before  any  significant  action 
can  be  observed  on  the  nerve  fiber.  Curara  in  larger  doses  may 
influence  ganglion  cells  or  other  parts  of  the  nervous  system,  but 
its  main  action  is  on  the  motor  endings  to  striated  muscle. 

Since  the  experiments  above  definitely  locate  the  action  of  curara 
on  the  nerve-endings,  and  since  physostigmin  counteracts  the  action 
of  the  curara,  its  action  is  on  the  same  point.  (For  the  probable 
mechanism  of  this  action,  see  Meyer  and  Gottlieb,  Dixon,  Cushny 
and  Sollmann.) 


PLATE   V. 


Vagus  Center 

Vaso  Motor 

Center 
Cervical 
Sympathetic 


COCAINE. 

The  poisonous  effects  of  Coca, 
or  the  secondary  effects  of  a  large 
dose,  aie  depressant,  following 
quite  definitely  the  lines  of  pre- 
vious stimulation. 

Nervous  System. 

Brain.  Cerebral  functions  are 
first  stimulated,  then  de- 
pressed, frequently  with  pro- 
duction of  narcosis  or  con- 
vulsions. 

Medulla.  Depi-esses  respira- 
tory center  and  probably 
vaso-motor  center. 

Spinal  cord.  Depresses  re- 
flex centers. 

Circulation.  Arterial  pressure  is 
lessened. 

Heart.  Depressed  by  direct 
action  of  the  drug. 

Capillary  area.  Arterioles 
relaxed,  probably  through 
paralysis  of  vasomotor  cen- 
ter. 
Eye  is  dilated.  Acts  as  a  nerve 
block. 

Respiration.  Depresses  the  respi- 
ratory functions  by  lessening 
the  irritability  of  the  center 
in  the  nieduila. 

In  genei'al,  the  depressant  ac- 
tion is  that  of  a  general  proto- 
plasmic poison,  the  commonest 
evidence  of  which  is  its  paral- 
yzant influence  upon  nerve  tissue 
when  locally  applied.  The  sen- 
sory nerves  are  more  susceptil>le. 


For  local  analgesic  purposes  the 
alkaloid  Cocaine  is  employed  in 
from    \   to  4  per  cent,  solutions. 
It  acts  ])y  blocking  the  sensory 
The  bliK^  color  indicates  the  depressant  eCTccts  of  a  toxic    impulses  so  that  they  never  reach 
dose  of  (-'ocainc.  the  brain  or  pain  area- 


CHAPTER   XI. 
PHARMACOLOGY  OF  SENSORY  NERVE   ENDS. 

COCAIN. 

Only  the  aconitin  group  of  drugs  has  an  action  on  afferent 
nerve-ends  (receptive  surfaces)  when  given  by  mouth  or  intra- 
venously. The  local  anesthetic  action  of  cocain  is  obtained  only 
by  the  direct  application  of  the  drug.  It  is  used  in  medicine  princi- 
pally for  its  local  action.  If  sufficient  is  given  systemically  the 
animal  dies  from  a  central  action  before  the  receptive  surfaces 
are  influenced. 

Experiment  I.^ — Cut  a  piece  of  filter  paper  about  2  cm.  square; 
dip  it  in  1  per  cent,  cocain  solution  and  apply  to  the  side  of  the 
tongue.  In  a  few  minutes  compare  the  sensitivity  of  this  point 
with  that  of  the  other  side. 

Experiment  II. — (a)  Place  2  to  3  drops  of  1  per  cent,  cocain  hydro- 
chloride in  the  eye  of  a  rabbit;  in  a  few  minutes  test  the  corneal 
reflex  and  sensitivity  of  the  eye  and  compare  it  with  the  normal. 

(6)  After  injection  of  cocain,  note  the  size  of  the  pupil  and  con- 
dition of  the  eyeball.     Explain. 

Experiment  HI. — Inject  hypodermically  into  the  leg  of  a  dog 
0.1  per  cent,  solution  of  cocain  hydrochloride  according  to  Shleich's 
method  and  determine  whether  you  can  operate  in  this  part  without 
causing  pain. 

Experiment  IV. — Repeat  III,  using  prococain  or  other  cocahi 
substitute. 

Experiment  V. — Inject  cocain,  0.5  c.c.  of  0.5  per  cent,  cocain 
hydrochloride  into  the  lymph  sac  of  a  frog  and  note  results.  ^ 

Experiment  VI. — Count  respiration  and  heart-rate  in  a  dog. 
Note  condition  of  the  pupil;  inject  5  c.c.  of  0.5  per  cent,  cocain 
intravenously  and  in  five  minutes  again  take  records. 

Experiment  VII. — ^Take  records  of  the  frogs  and  turtle  heart  by 
the  suspension  method.  Irrigate  with  O.OI  per  cent,  cocain  hydro- 
chlorifle  in  normal  saline  and  note  results  in  the  tracing. 

Experiment  VIII. — Prepare  turtle  heart  strips  and  take  tracings 
of  the  coiitnictiojis  in  0.8  per  cent.  NaCl.  Rej)]ace  with  saline  con- 
taining 0.01  per  cent,  cocain  solution.    What  is  the  result? 


148  PHARMACOLOGY  OF  SENSORY  NERVE  ENDS 

Experiment  K. — Ligate  one  leg  of  a  frog  as  high  up  as  possible. 
Inject  0.5  c.c.  of  0.5  per  cent,  cocain  into  the  dorsal  lymph  sac. 
In  thirty  minutes  prepare  the  muscles  of  both  legs  for  superimposed 
tracings,  weighting  both  muscles  to  the  same  extent,  about  50  grams, 
and  stimulate  the  nerves  by  the  same  electrode.  Take  tracings  on 
a  slowly  moving  drum  and  note  which  muscle  fatigues  first  (see 
Fig.  25.) 

Experiment  X. — 1 .  Effect  of  cocain  on  the  circulation  and  respira- 
tion of  a  mammal;  anesthetize  a  mammal  with  ether;  insert  tracheal 
cannula  and  prepare  for  respiratory  and  blood-pressure  tracings. 
Inject  1  c.c.  of  1  to  10,000  epinephrin.    Repeat  after  five  minutes. 

2.  Inject  5  c.c.  of  0.5  per  cent,  cocain  intravenously;  note  effect 
on  the  heart,  respiration  and  eye. 

3.  In  three  minutes  repeat  the  injection  of  epinephrin.  Is  there 
any  difference  in  the  height  or  character  of  the  epinephrin  curve? 

Experiment  XI. — Spinal  Anesthesia. — Without  the  use  of  an 
anesthetic  inject  0.1  per  cent,  cocain  or  1  per  cent,  prococain  or  any 
other  cocain  substitute  into  the  membranes  of  the  cord  in  the 
lumbar  region  of  a  dog.  Use  a  thin  needle.  In  five  minutes  test  the 
sensitivity  in  the  hind  legs.  What  are  the  dangers  of  spinal  anes- 
thesia?   Can  an  animal  walk  if  the  feet  are  anesthetized ?    Explain. 

Experiment  Xn. — Action  of  Cocain  on  the  Temperature. — ^Take 
the  rectal  temperature  of  a  dog  or  rabbit.  Inject  1  c.c.  per  kilo  of 
5  per  cent,  cocain  intravenously  in  the  dog  or  2  c.c.  hypodermically 
in  the  rabbit.  Take  temperature  every  ten  minutes  for  four  times. 
If  the  animal  is  not  in  convulsions,  repeat  the  injection  until  definite 
symptoms  occur.    Make  a  notation  of  the  variation  from  the  normal. 

Treatment  of  cocain  poisoning.    This  is  purely  symptomatic. 

Local  Anesthesia  in  Man. — Sterilize  a  small  hypodermic  syringe 
and  needle  by  boiling.  In  the  same  way  boil  about  10  c.c.  of  2  per 
cent,  cocain  hydrochloride  for  two  minutes. 

Boil  needles  for  testing  sensation  in  the  same  way.  Wash  the 
skin  of  the  arm  with  soap  and  water,  alcohol,  ether  and  finally 
paint  with  tincture  of  iodin.  Inject  about  0.2  to  3  c.c.  of  the  cocain 
solution,  under  the  painted  area,  with  aseptic  precaution.  In  a 
minute  test  the  sensation  to  the  prick  of  the  needle. 


CHAPTER  XII. 
AUTONOMIC  SYSTEM  AND  AUTONOMIC   DRUGS. 

Those  drugs  which  act  especially  on  the  autonomic  sympa- 
thetic or  the  sympathetic-parasympathetic  systems  are  known  as 
autonomic  drugs.  The  used  nomenclature  of  this  system  is  not 
definitely  established.  At  present  it  is  current  only  among  physiol- 
ogists and  pharmacologists.  Anatomists  are  not  yet  agreed  on  it, 
and  it  is  still  in  a  state  of  change.  The  classification  is  based  mainly 
on  the  reaction  of  parts  of  the  nervous  system  to  the  action  of  drugs, 
and  these  reactions  are  so  striking  and  constant  that  they  must 
indicate  fundamental  anatomical  differences.  The  unstable  condi- 
tion of  the  nomenclature  is  due  to  the  newness  of  this  field  and  the 
minor  changes  which  detailed  investigation  always  brings. 

Langley  has  done  most  work  on  this  system  and  the  nomenclature 
is  due  for  the  most  part  to  him.  He  divides  the  involuntary  nervous 
system,  or  the  vegetative  nervous  system,  into — 

1.  Autonomic  or  parasympathetic. 

2.  Sympathetic. 

3.  Enteric  system. 

The  great  difference  between  this  system  and  the  mhintary 
system  is  that  in  the  voluntary  system  the  motor  fibers  go  direct 
from  the  anterior  horn  cells  to  the  end-organ  or  the  effector  organ. 
In  the  involuntary  nervous  system  the  nerve  fibers,  after  leaving 
the  central  nervous  system,  first  pass  to  a  ganglion  before  going  to 
the  end-organ.  Just  why  we  have  control  over  the  organs  that 
receive  their  nerve  supply  direct  from  the  central  system  and  have  no 
control  over  those  innervated  by  the  sympathetic  is  not  known.  So 
far  as  we  know  there  is  no  reason  for  the  difference. 

Differences  between  the  Sympathetic  and  Parasympathetic  System. 
—The  sympathetic  system  leaves  the  cord  from  the  first  thoracic  to 
the  fourth  or  fifth  lumbar.  They  include  vasomotor,  sweat,  pilo- 
motor and  secretory  fibers.  The  system  differs  anatomically, 
embryologically,  physiologically  and  pharmacologically  from  the 
parasympathetic  system. 

The  Parasympathetic  System.— The  parasympathetic  system  is 
also  called  the  craniosacral  autonomic  system  or  the  craniobulbar 


150 


AUTONOMIC  SYSTEM  AND  AUTONOMIC  DRUGS 


and  sacral  sympathetic  systems.  The  fibers  forming  this  system  arise 
from  the  brain,  medulla  and  midbrain  and  are  carried  especially  in 
the  third,  seventh,  ninth,  tenth  and  eleventh  cranial  nerves.  The 
sacral  part  of  this  system  leaves  the  central  system  mainly  in  the 


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pathetic fibers  are  indicated  by  dotted  Unes;  parasympathetic  (autonomic)  by 
unbroken  lines.     (Kraus,  modified  from  Meyer  and  Gottlieb.) 


AUTOXOMIC  SYSTEM  AXD  AUTONOMIC  DRUGS 


151 


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152         AUTONOMIC  SYSTEM  AND  AUTONOMIC  DRUGS 

first  sacral  nerve,  and  the  N.  pelvicus  supplies  the  descending  colon, 
rectum,  anus,  bladder  and  genital  organs. 

The  Enteric  System. — The  enteric  system,  which  controls  the 
autonomic  movements  of  the  hollow  viscera,  receives  fibers  from 
both  the  sympathetic  and  the  parasympathetic  systems,  but  is  not 
yet  sufficiently  marked  to  consider  it  as  an  independent  system. 


AUTONOMIC  DRUGS. 

I.  The  drugs  which  act  especially  on  the  autonomic  system  are 
the  atropin  group,  the  pilocarpin,  eserin  groups  and  choline.  These 
drugs  act  especially  on  the  yarasympathetic  system. 

II.  The  epinephrin  group  of  drugs,  which  act  on  the  sympathetic. 

III.  The  nicotin  group,  which  acts  especially  on  the  ganglion 
cells  and  acts  on  all  ganglion  cells  of  both  systems. 

IV.  Morphin  acts  on  the  enteric  system.  The  action  is  peripheral 
on  Auerbach's  plexus.  This  is  the  only  undoubted  peripheral  action 
of  morphin. 

The  chief  actions  of  atropin  are:  Paralysis  of  the  parasympa- 
thetic nerve-endings,  with  consequent — 
Dilation  of  the  pupil. 
Eapid  heart. 

Xerostomia  due  to  suppression  of  the  saliva. 
Anhydrotic  action. 
Suppression  of  the  mucous  secretion. 
Diminution  of  the  gastric  and  the  intestinal  secretions. 
Suppression  of  excessive  peristalsis. 
Antagonistic  action  to  eserin,  pilocarpin,  etc. 

ATROPIN  AND  PILOCARPIN  GROUP. 

Experiment  I. — Take  a  normal  dog,  count  the  pulse  and  respiration 
-and  note  the  size  of  the  pupil  and  the  flow  of  the  saliva.  Give  him 
a  hypodermic  injection  of  0.5  c.c.  of  1  per  cent,  pilocarpin  nitrate. 
Note  the  effect  on  respiration,  heart-rate,  pupils  and  salivary  flow. 
When  a  marked  flow  of  saliva  has  been  obtained,  inject  1  c.c.  of 
0.1  per  cent,  atropin  sulphate  and  make  observations  again. 

Experiment  II. — ^This  experiment  may  be  done  only  when  it  is 
desirable  to  study  the  mechanism  of  atropin  action.  Anesthetize 
a  dog,  cat  or  rabbit  and  prepare  for  blood-pressure  and  respiratory 
tracing  and  for  vagus  stimulation.  Insert  a  cannula  in  Wharton's 
duct  and  isolate  the  chorda  tympani  and  prepare  for  stimulating  it. 


PLATE  VI 


BELLADONNA. 

Leaves  and  root  of  Atropa  B.     The  alkaloid  Atropine  represents  tlie  drug  fully. 

Classified  as : 

Cerebral  stimulant.  Deliriaiit  narcotic.  Mydriatic. 

Cardiac  stimulant.  Anodyne.  Antihidrotic. 

Physiologic  action  : 

In  general,  '"  atropine  acts  as  a  stimulant  to  the  central  nervous  system  and  paralyzes  the 
terminations  of  a  number  of  the  nerves,  more  especially  of  those  that  supply  invol- 
untary muscle,  secretory  glands  and  the  heart."  [Cushny.]  It  paralyzes  peripheral 
inhibition.  It  decreases  the  secretions  generally,  except  the  urine,  and  increases  the 
body  temperature,  producing  a  condition  simulating  fever. 

Nervous  System. 

Brain.     Stimulates  the  cerebrum,  especially  in  its  motor  areas. 
Medulla.     Stimulates  respiratory  and  vasomotor  centers. 
Spinal  cord.     Depresses  inhibitory  centei's. 

Nerves.' 

Sensory.     Depresses  sensory  nerve  endings. 
Motor.     Depresses  motor  nerves. 

Secretory.     Paralyzes  the  endings  of  many  of  the  secretory  nerves,  causing  a  diminu- 
tion or  arrest  of  the  secretion ;  hence  there  result  dryness  of  the  mouth,  lessened 
secretion  of  gastric  and  pancreatic  j  uices  and  of  milk.    The  sweat  glands  are  rendered 
less  active. 
Vagus.     Paralyzes  the  inhibitory  terminations  of  the  vagus  within  the  heart,  and  the 
secretory  terminations  within  the  digestive  system. 
Muscular  System.     Depresses  unstriped   muscle,  but  has  no   influence   upon   voluntary 
muscle.     Lessens  the  movements  of  stomach,  intestines,  bladder,  uterus,  and  in  gen- 
eral the  organs  containing  unstriped  muscle,  except  the  arterial  walls.     [Cushny.] 
Eye.     Pupils  are  dilated  by  paralysis  of  terminals  of  the  motor  oculi  nerve  in  the  iris, 
with  possible  stimulation  of  the  sympathetic  terminals.     It  paralyzes  accommodation. 
Most  authorities  state  that  it  increases  inti-aocular  pressure. 
Circulation.     Arterial  pressure  is  increased,  chiefly  by  centi-al  vasomotor  stimulation. 
Heart.     Increases  pulse  rate  by  paralyzing  inhibition   (peripheral  ends  of   vagus). 

The  heart  muscle  or  its  accelerator  nerves  may  feebly  be  stimulated. 
Capillary  area.     Arterioles  are  contracted. 
Respiration.     Stimulated  by  action  upon  respiratory  center. 

Excretion.  Perspiration  is  lessened.  The  drug  is  excreted  rapidly  by  the  kidneys,  but 
its  influence  upon  their  activity  is  uncertain. 


PLATE  VI 


Arterioles 
contracted 


Sweat  glands 

less  active- 

Motor  nerves 
and  sensory 
nerve  endings 
depressed. 


Varjus  Center 

Vaso  Motor 

Center 
Cervical 
SympathetiG, 


Solar  Plexus 


Pelvic  Plexus 


Tlic  rcil  color  iiii?iciitcs  stiiniiliitioM,  iiiid  the,  liliic  color  (lci)rcssion 


ATROPIX  AXD  PILOCARPIN  GROUP 


153 


1.  Take  normal  tracings. 

2.  Stimulate  the  chorda  tympani;   stimulate  the  vagus. 

3.  Stimulate  both  simultaneously. 

4.  Inject  0.5  c.c.  pilocarpin  nitrate  intravenously.  Note  results 
in  the  eye,  saliva,  heart,  respiration  and  blood-pressure.  Stimulate 
the  chorda  and  vagus  separately.  Inject  0.5  c.c.  of  1  per  cent, 
atropin  sulphate  and  repeat  stimulations. 


Wharton)s  duct 


Parihohn's  duct 
Lingual  nerves 


/^ylo-hyoid  muscle 


Chorda  tympani^^ 
Xtylo-hyoid  wax. 


-,^g^tAyP:vJ     Hypoglossal  nerve 


Fig.  35. — Dissection  to  show  region  of  Wharton's  duct.     The  lingual  and  chorda 
tj-mpani  nerves  are  sometimes  called  the  chorda  linguae  in  descriptions. 


5.  When  .stimulation  of  the  chorda  gives  no  saliva,  place  the 
electrfxles  in  the  hilus  of  the  gland  and  stimulate.  Stimulation  of 
the  s\-mpathetics,  either  with  the  electrodes  or  with  adrenalin,  still 
causes  a  flow  of  saliva,  hence  the  gland  cells  are  not  paralyzed. 
The  action,  therefore,  is  not  on  the  gland  cells.  Either  isolate  and 
stimulate  the  cervical  sympathetic,  peripheral  to  the  superior  cer- 
vical ganglion  or  give  the  animal  1  c.c.  of  1  to  10,000  epinephrin 
and  note  the  results  on  the  saliva. 

Experiment  Til.— Effect  of  Atropin  on  the  Eye.— Take  a  number  of 
animals— dog,  cat,  rabbit,  guinea-pig,  chicken  or  pigeon— and  drop 
1  per  cent,  atropin  sulphate  in  one  eye  and  1  per  cent,  eserin  in  the 


154 


AUTONOMIC  SYSTEM  AND  AUTONOMIC  DRUGS 


other.  Record  the  action.  Take  a  frog,  pith  and  remove  the  eyes. 
Place  one  in  a  solution  of  1  per  cent,  atropin  and  the  other  in  a  solu- 
tion of  1  per  cent,  pilocarpin  or  eserin;  set  in  a  dark  place.  Why  in 
a  dark  place?    Compare  and  record  the  results  on  all  animals. 

Experiment  IV. — Action  of  Atroinn  on  the  Frog  and  Turtle  Heart. — 
1.  Take  a  frog  and  turtle  and  isolate  the  heart  and  vagus.  Take 
a  tracing  by  the  suspension  method.  Stimulate  the  vagus.  Now 
apply  1  per  cent.  pilocarpin"and  again  stimulate  the  vagus.  Repeat 
this  several  times. 

2.  Apply  1  per  cent,  atropin  and  again  stimulate  the  vagus. 
When  the  vagus  stimulation  is  ineffective,  again  apply  pilocarpin. 
What  is  the  result?  Discuss  the  antagonism  of  atropin  and  pilo- 
carpin. 


VAGUS  NERVE 


R.AURICLE 
SINUS  VENOSUS 


PERIOR  VENA  CAVA 


Fig.  36. — Relation  of  the  vagus  nerve  in  the  frog  as  modified  from  Schafer. 


Experiment  V. — Action  of  Pilocarjnn  and  Atropin  on  Turtle  Heart 
Strips. — Set  up  heart  strips  in  saline  in  the  usual  way.  When  the 
contractions  are  regular  add  a  1  per  cent,  solution  of  pilocarpin 
nitrate  in  saline  until  the  bath  around  the  strip  is  0.1  per  cent,  of 
pilocarpin.  After  thirty  minutes,  or  when  good  records  are  obtained, 
replace  the  bath  with  normal  saline. 

When  contractions  are  again  regular,  add  1  per  cent,  atropin 
in  successive  amounts  until  the  bath  contains  0.001,  0.01  and  0.1 
per  cent,  atropin  sulphate. 

Experiment  VI. — ^Repeat  Experiment  V,  using  the  atropin  before 
the  pilocarpin. 


ATROPIN  AND  PILOCARPIN  GROUP  155 

Experiment  Vn. — Use  physostigmin  salicylate  instead  of  pilo- 
carpin  nitrate  (a)  before  atropin  and  (6)  following  atropin. 

Experiment  Vin.^ — Effect  of  Atropin  and  Pilocarpi7i  on  the  Volume 
of  the  Respired  Air. — 1.  This  experiment  may  be  carried  out  in 
connection  with  some  of  the  previous  experiments;  anesthetize  the 
animal  and  arrange  for  blood-pressure  and  respiration  tracings. 
Take  the  respiration  tracing  from  a  band  around  the  chest  or  abdo- 
men. Insert  a  tracheal  cannula  for  connection  with  a  spirometer. 
Take  normal  tracing  and  measure  the  volume  of  expired  air  per 
minute  and  the  rate  of  respiration. 

2.  Inject  slowly  1  c.c.  of  0.5  per  cent,  pilocarpin  nitrate  intra- 
venously and  note  change  in  blood-pressure,  heart-rate,  respiration- 
rate  and  volume.  Repeat  injection  if  necessary.  After  fifteen 
minutes,  measure  the  respiratory  volume  and  inject  slowly  0.1  per 
cent,  physostigmin  until  the  first  effect  of  the  blood-pressure  is 
noticed.    IMeasure  the  respiratory  volume  again. 

3.  Now  inject  1  c.c.  of  0.5  per  cent,  atropin  sulphate  and  record 
the  influence  on  the  heart  and  respiration.     Repeat  if  necessary. 

Experiment  IX. — Action  of  Pilocarpin,  Physostigmin  and  Atropin 
on  Uterine  Strips. — Remove  the  uterus  from  a  guinea-pig,  cat  or 
rabbit  and  place  it  in  warm  saline  and  keep  a  current  of  air  or 
oxygen  running«through  the  saline.  Movmt  a  small  piece  of  it  in 
warm  saline  and  take  a  record  of  the  contractions.  When  contrac- 
tions are  regular  add  pilocarpin  until  the  solution  contains  0.01 
per  cent,  then  0.1  per  cent.  What  is  the  result?  Now  change  the 
saline  and  when  contractions  are  regular  add  0.001  per  cent,  atropin 
sulphate,  0.01  and  0.1  per  cent,  and  note  results. 

Experiment  X. — Repeat  Experiment  IX,  using  atropin  first. 

Experiment  XI. — Repeat  Experiment  IX,  using  physostigmin  0.01 
and  0.1  per  cent,  instead  of  pilocarpin. 

Experiment  XII. — Action  of  Atropin  and  Physostigmin  on  the 
Intestinal  Movement. — From  the  animal  used  in  the  previous 
experiments,  carefully  remove  rings  of  the  small  intestine  and  take 
tracings  as  with  uterine  strips.  To  obtain  the  best  contractions  an 
adequate  weight  must  be  applied.  The  best  condition  can  only  be 
obtained  by  experimenting.  Use  the  same  drugs  as  in  the  uterine 
strips. 

Experiment  Xni. — Use  a  dog  that  has  been  one  day  without  food. 
Insert  a  tracheal  cannula  and  attach  to  an  ether  bottle. 

1.  Pith  the  dorsal  spinal  cord  in  the  following  manner:  Cut  down 
to  the  lainijiji'  of  the  first  and  second  lumbar  vertebra',  detaching 
the  muscles  from  the  spinous  processes.    With  bone  forceps  remove 


156 


AUTONOMIC  SYSTEM  AND  AUTONOMIC  DRUGS 


these  processes  and  the  laminse  (controlling  hemorrhages  with 
pledgets  of  cotton  saturated  with  ferric  sulphate  solution,  5  per 
cent.),  exposing  the  spinal  cord.  With  rotary  motion  insert  ante- 
riorly a  soft  wire  with  the  end  recurved  to  form  an  open  hook  about 
4  or  5  mm.  across.  Eemove  the  wire.  Insert  a  cotton  pledget  and 
close  the  incision  (see  Fig.  17). 

2,  Prepare  the  gut  for  tracings  as  described  under  epinephrin. 
Experiment  IV  (2)  (page  167). 


Fig.  37. — ^Apparatus  for  recording  contractions  of  uterine  or  intestinal  strips. 
The  air  is  supplied  through  a  hypodermic  needle.  Instead  of  the  siphon  a  vessel 
may  be  prepared,  where  the  outlets  can  be  made  directly  through  the  vessel  wall. 

3.  Arrange  for  injections  into  the  femoral  vein  with  a  burette. 
Take  preliminary  control  tracings,  one  complete  revolution,  showing 
at  the  beginning  the  effect  of  (1)  lifting  gut;  (2)  inserting  a  needle 
into  the  gut;  (3)  replacing  the  gut  and  at  another  place  the  intro- 
duction of  Ringer's  solution  into  the  abdominal  cavity  at  body 
temperature.  Note  the  effects  of  respiration  on  the  curve.  Then 
note  the  effects  of  the  following  procedures : 

1.  Injection  of  20  c.c.  of  5  per  cent.  NaCl  solution  into  the  lumen 
of  the  gut  (one  revolution). 

2.  Intravenous  injection  of  pilocarpin  solution,  1  c.c.  of  1  to  1000. 

3.  Intravenous  injection  of  5  c.c.  of  0.5  per  cent,  atropin  sulphate. 


N I  COT  IN  157 

Experiment  Xr7. — Antagonism  of  Atropin  to  Morphin. — 1.  Take 
the  normal  respiration  and  heart-rate  of  a  dog.  Note  the  condition 
of  the  pupil.  Give  him  a  hypodermic  of  1  c.c.  of  3  per  cent,  morphin 
sulphate.    After  thirty  minutes  repeat  the  records. 

2.  Give  an  intravenous  injection  or  a  hypodermic  of  atropin 
sulphate,  1  c.c.  of  0.5  per  cent.,  and  again  make  records.  If  the 
animal  is  much  depressed  from  the  morphin  give  the  atropin 
intravenously. 

Experiment  XV. — Students  will  divide  into  groups.  Count  the 
heart  and  the  respiratory  rate.  Note  the  size  of  the  pupil,  condition 
of  skin,  reflexes,  etc. 

Group     I.  Each  pupil  take  |  grain  (0.01  gram  of  pilocarpin.) 
II.  I  grain,  0.02  gram. 
Ill,  5  grain,  0.03  gram. 

Observe  as  above  until  sweating  commences.  If  sweating  is 
excessive  take  j^-^  grain  of  atropin  every  fifteen  minutes  until 
sweating  is  arrested.  Do  not  take  more  than  two  doses  of  the 
atropin  unless  sweating  is  excessive. 

Groups  IV,  V  and  VI.  Take  t¥o"  grain  of  atropin  first,  then 
after  fifteen  minutes  take  the  amount  of  pilocarpin  used  by  Groups 
I,  II  and  III. 

NICOTIN. 

Nicotin,  like  curara,  is  an  important  drug  in  research  work  and 
in  illustrating  selective  action.  Because  of  the  widespread  use  of 
tobacco  the  action  of  nicotin  is  important  from  an  economic  point 
of  view.  It  is  also  a  violent  poison.  Its  first  action  is  on  the  ganglion 
cells.  All  ganglion  cells,  sympathetic  and  parasympathetic,  are 
acted  upon. 

Experiment  I. — To  show  the  selective  action  of  nicotin  on  the 
ganglion  cells:  Anesthetize  a  rabbit,  cat  or  dog  and  dissect  the 
cervical  sympathetic  and  lay  bare  the  superior  cervical  ganglion. 
Stimulate  the  nerve  below,  on,  and  peripheral  to  the  ganglion. 
Note  the  dilation  of  the  pupil  and  the  constriction  of  the  ear  vessels. 
Paint  the  nerve  below  the  ganglion  with  1  per  cent,  nicotin.  Stimu- 
lation over  this  painted  area  or  below  it  shows  no  block  of  the 
impulse.  Now  paint  the  ganglion.  In  a  few  minutes  stimulation 
below  or  on  the  ganglion  shows  that  the  impulses  are  blocked  while 
stimulation  peripheral  to  the  ganglion  still  gives  dilation  of  the 
pupil  and  dilation  of  the  ear  vessels.  If  the  animal  is  in  condition, 
prepare  for  blood-pressure  and  respiration  as  in  Experiment  II. 


158 


AUTONOMIC  SYSTEM  AND  AUTONOMIC  DRUGS 


Experiment  II. — Prepare  a  dog  or  rabbit  for  blood-pressure  and 
respiration  tracings  and  for  stimulation  of  the  vagus. 

1.  Inject  intravenously  1  c.c.  of  1  to  10,000  epineplirin.     Note 
results  on  heart-rate j  blood-pressure  and  respiration. 

2.  Stimulate  the  vagus  again, 

3.  Inject  5  c.c.  of  0.1  per  cent,  nicotin  solution  and  note  the  effect 
on  the  heart-rate,  blood-pressure  and  respiration. 


Carotid  arter2J_ 


Trachea- 


Subc^civianA 


Cervical  sj/mpaiheticN. 

Vagrus  nerve 

J)epressor  nerve 


Inf.  cervical  otrnalia 
.VeriehralA 

;^^^. ...  SviclavianA 

.  Thvracicffanylia 

Tfioracic   sym 
Rec  Ictrn/zqeal    ntrve 

Va(^us  nerve 


Fig.  38. — Diagram  of  inferior  cervical  and  thoracic  ganglia  in  the  rabbit. 
(After  Foster.) 

4.  Stimulate  the  vagus  again.     If  it  is  still  active  repeat  the 
injection  of  nicotin. 

5.  Inject  1  c.c.  of  1  per  cent,  pilocarpin  nitrate  and  note  effect 
as  before. 

6.  Stimulate  the  vagus  again. 

7.  Inject  5  c.c.  of  0.1  per  cent,  nicotin  solution  again  in  five 
minutes. 

8.  Inject  1  c.c.  of  1  per  cent,  atropin  sulphate  and  note  the  influ- 
ence on  the  heart-rate,  blood-pressure  and  respiration. 

9.  Stimulate  the  vagus  again. 

10.  Inject  5  c.c.  of  0.1  per  cent,  nicotin  solution  and  compare  the 
effect  with  previous  injections. 

11.  Inject  1  c.c.  of  1  to  10,000  epinephrin.    Discuss  results. 
Experiment  III. — Inject  1  c.c.  of  0.1  per  cent,  nicotin  into  the  lymph 

sac  of  a  frog.    Note  and  make  diagrams  of  the  position  of  the  animal 
from  time  to  time.    Note  the  twitchings  of  the  muscles.    What  is 


NICOTIN  ]59 

the  infiiience  of  cutting  the  sciatic  on  the  twitchings?    Stimulate 
the  peripheral  end  of  the  sciatic. 

2.  Compare  this  action  on  the  muscles  with  that  of  another  frog 
in  which  one  injects  1  c.c.  of  1  per  cent,  physostigmin.  Twitchhigs 
of  the  muscles  should  develop  in  this  animal,  too,  but  they  do  not 
stop  when  the  nerve  is  cut.  Curara  causes  the  physostigmin 
twitchings  to  stop.   Strong  ■MgS04  also  causes  them  to  stop. 

Experiment  IV .—Demonstration;  Nicotin  in  Tobacco  Smoke.— 
The  main  active  ingredient  of  tobacco  smoke  is  nicotin.  To  show 
the  nicotin-like  action  of  tobacco  smoke,  place  a  couple  of  frogs  in 
a  large  bottle  or  under  a  bell- jar  and  insert  a  two-holed  stopper  in 
the  vessel  used.  In  one  hole  place  a  pipe  or  thistle  tube  containing 
tobacco.  In  the  other  place  a  glass  tube  reaching  to  the  bottom 
of  the  vessel.  Attach  a  rubber  tube  to  the  glass  tube  and  light  the 
tobacco.  Aspirate  the  smoke  into  the  bottle  and  notice  the  influence 
on  the  frogs.  Compare  these  animalg  with  those  that  got  pure 
nicotin. 

Experiment  V. — Place  one  drop  of  nicotin  on  the  tongue  of  a 
mouse,  guinea-pig  or  other  small  animal  and  notice  effect. 

Experiment  VI.— Count  the  respiration  and  heart-beat  and  note 
the  size  of  the  pupil  and  the  salivary .  flow  in  a  dog.  Give  intra- 
venously, without  an  anesthetic,  5  c.c.  of  0.01  per  cent,  nicotin 
and  note  the  changes.     Repeat  injection  of  nicotin  if  necessary. 

Experiment  VII. — Anesthetize  a  dog  and  inject  0.5  c.c.  of  0.1  per 
cent,  nicotin  into  the  lumbar  cord.    Note  the  result  on  the  reflexes. 

Experiment  Vin. — The  influence  of  nicotin  in  modifying  the  tracing 
of  epinephrin.  Take  the  blood-pressure  in  a  dog  hi  the  usual  way. 
Inject  0.5  c.c.  of  1  to  10,000  epinephrin  into  the  femoral  vein.  When 
the  pressure  returns  to  normal  give  0.025  c.c.  of  1  per  cent  nicotin 
solution  and  record  the  effect  on  the  blood-pressure.  Alternate  the 
epinephrin  and  nicotin  injections  until  definite  results  are  obtained. 
After  a  time  nicotin  gives  no  rise  of  blood-pressure,  but  epinephrin 
is  still  effective.    How  do  you  explain  these  actions? 

Note.— See  Epinephrin,  page  IGG,  which  should  be  included  in 
autonomic  drugs. 


CHAPTER  XIII. 
PHARMACOLOGY  OF  THE  EYE. 

Function. — Vision. 

Essential  Organ. — The  retina  and  optic  nerve. 

Accessory  Organs. — ^The  internal  and  external  muscles,  lacrimal 
glands,  lens,  etc. 

The  retinal  ganglionic  layer  may  be  considered  similar  to  the 
spinal  sensory  ganglion  cells.  The  peripheral  parts  being  receptive 
endings  and  the  optic  nerve  the  continuation  centralward  of  the 
afferent  nerve. 

These  facts  explain  why  methyl  alcohol,  quinin,  santonin,  tobacco, 
male  fern,  alcohol,  pelletierin,  carbon  bisulphide,  napthols,  etc., 
which  injure  the  retinal  ganglion  cells  may  also  injure  the  optic 
nerve. 

Drug's  Acting  on  the  Lacrimal  Glands. — ^The  atropin  group  causes  a 
lessened  secretion  of  tears. 

The  pilocarpin  group  stimulates. 

In  eye  work  when  these  drugs  are  used  the  drying  effect  of  atropin 
is  not  a  serious  drawback  in  the  use  of  the  drug.  After  large  doses 
of  pilocarpin  the  tears  are  markedly  stimulated.  However,  moisten- 
ing of  the  eyeball  is  not  due  entirely  to  the  lacrimal  glands  because 
after  their  removal  or  disintegration  the  eye  does  not  become  dry. 
The  secretion  of  the  conjunctiva  itself  and  its  mucous  glands  aid 
in  the  moistening  of  the  eye. 

The  nerves  to  the  lacrimal  glands  are  the  lacrimal,  a  branch  of 
the  ophthalmic  nerve,  which  in  turn  is  one  of  the  three  primary 
divisions  of  the  fifth  nerve,  a  parasympathetic  nerve. 

Drugs  Stimulating  the  Retinal  Cells  or  Vision. — Strychnin  increases 
the  acuteness  and  also  enlarges  the  field  of  vision. '^ 

The  caffein  group  of  drugs  have  a  similar  action. 

Drugs  Depressing  the  Retinal  Function. — Drugs  are  not  known  that 
definitely  reduce  the  retinal  hyperesthesia  with  severe  pain.  Pain 
arising  from  the  conjunctiva  may  be  reduced  by  the  local  application 
of  cocain  and  by  the  central  action  of  the  alcoholic  group  or  morphin. 

1  Filenhe:  Pfliiger's  Archives,  1901,  vol.  iii. 


PHARMACOLOGY  OF  THE  EYE  161 

The  Iris  and  the  Ciliary  Muscle. — The  function  of  these  is  to  con- 
strict and  enlarge  the  pupil,  hence  to  regulate  the  amount  of  light 
that  reaches  the  retina  (see  Fig.  19,  page  99).  The  iris  consists  of 
two  sets  of  muscle  fibers:  (1)  circular  and  (2)  radiating. 

Stimulation  of  the  constrictor  fibers  narrows  the  pupil.  The  third 
nerve  governs  the  action  of  the  circular  muscle  fibers  while  the 
sympathetic  system  governs  the  radiating. 

Any  of  the  drugs  acting  on  smooth  muscle  would  act  on  the 
muscles  of  the  eye  if  applied  directly;  practically,  however,  direct 
muscular  action  is  unimportant.  The  important  action  is  due  to 
an  action  on  the  nerves. 

Drugs  Stimulating  the  Third  Nerve  (Parasympathetic  Endings). — 
(1)  Eserin  and  (2)  pilocarpin. 

Drugs  Paralyzing  the  Third  Nerve  Endings. — (1)  Atropin  and  (2) 
substitutes. 

Drugs  Stimulating  the  Sympathetic  Nerves  to  Radiating  Fibers. — 
(1)  Epinephrin  and  (2)  cocain. 

Drugs  Paralyzing  the  Sympathetic  Nerve  Endings  in  the  Eye. — 
(1)  Cocain  in  large  amounts  paralyzes  all  nerve  endings.  Ergo- 
toxin  will  paralyze  the  constrictors.  However  these  actions  are 
not  especially  prominent  in  the  eye  and  are  psrhaps  little  in 
operation  here. 

Drugs  Changing  the  Size  of  the  Pupil  by  a  Central  Action. — 1. 
Morphin,  pin-point  pupil. 

2.  Chloral,  pin-point  pupil. 

3.  Asphyxia,  first  constricts  then  dilates. 

4.  Drugs  causing  dilation  due  to  paralysis  of  the  central  end  of 
the  third  nerve — certain  ptomains,  for  example,  fish,  muscles, 
cheese,  sausage,  etc. 

Proof  that  Atropin  Dilates  the  Pupil  by  Paralysis  of  the  Third  Nerve 
Endings. — 1.  The  action  is  peripheral  because  when  applied  to  the 
eye  locally  and  the  drug  is  kept  from  being  absorbed  it  dilates  the 
pupil. 

2.  It  will  dilate  the  pupil  after  degeneration  of  the  sympathetic 
nerve. 

3.  The  action  is  peripheral,  since  it  acts  on  the  enucleated  eye. 

4.  Stimulation  of  the  third  nerve  peripheral  to  the  ganglion  is 
not  effective  after  atropin,  though  active  before.  Direct  stimula- 
tion of  the  muscle  in  such  cases  is  eftective. 

5.  Atropin  antagonizes  the  action  of  eserin  and  pilocarpin. 
().  Atropin  has  no  action  on  the  sympathetic  nerves  to  the  eye. 
7.  It  is  not  known  to  have  any  action  on  the  muscles  of  the  eye. 

11 


162  PHARMACOLOGY  OF   THE  EYE 

Proof  that  Eserin  and  Pilocarpin  Stimulate  the  Third  Nerve  Endings. 
— 1.  They  act  on  the  enucleated  eye,  therefore  the  action  is  per- 
ipheral. 

2.  Stimulation  of  the  sympathetic  peripheral  to  the  superior 
cervical  ganglion  is  still  effective  after  these  drugs,  therefore  the 
action  is  not  due  to  a  paralysis  of  the  sympathetic. 

3.  The  action  does  not  occur  after  degeneration  of  the  nerves, 
therefore  it  is  not  on  the  muscle. 

4.  Direct  stimulation  of  the  muscle  still  produces  contraction. 

5.  The  opinion  that  the  action  is  on  the  nerve-endings  of  the  third 
nerve  is  corroborated  by  the  action  on  other  locations  innervated 
by  the  parasympathetics. 

Some  Differences  in  the  Action  of  Eserin  and  Pilocarpin. — ^The  chief 
differences  in  the  action  of  eserin  and  pilocarpin  are : 

1.  Pilocarpin  actually  stimulates  the  nerve-endings  while  eserin 
merely  sensitizes  the  endings  and  renders  them  very  responsive  to 
stimuli,  reaching  them  from  the  nerve.  The  basis  for  this  belief  is: 
If  the  chorda  tympani  nerve  be  cut,  eserin  often  fails  to  cause  secre- 
tion while  pilocarpin  causes  secretion. 

2.  Eserin  injected  into  Wharton's  duct  to  reach  the  endings 
directly  will  cause  no  secretion  if  impulses  from  the  center  are 
blocked  while  pilocarpin  causes  secretion. 

3.  Eserin  likewise  fails  to  contract  the  pupil  after  degeneration 
of  the  postciliary  branches,  while  pilocarpin  is  still  effective. 


CHAPTER   XIV. 
^  ANTAGONISM. 

By  antagonism  we  mean  counteraction  of  the  effects  of  one  drug 
by  another:    It  may  be  one  of  two  kinds: 
I.  Chemical. 
II.  Physiological. 

Chemical  antagonism  is  easily  understood  in  most  cases.  When 
gastric  hj^Deracidity  is  neutralized  by  sodium  bicarbonate  or  when 
the  action  due  to  the  intravenous  injection  of  an  acid  is  neutralized 
by  a  similar  injection  of  sodium  bicarbonate  the  explanation  is 
apparent.  Some  writers  call  this  chemical  antagonism,  distoxica- 
tion  or  neutralization,  and  reserve  the  term  antagonism  to  physio- 
logical actions, 

PHYSIOLOGICAL  ANTAGONISM. 

The  classic  example  of  antagonism  is  atropin  and  pilocarpin. 
So  far  as  we  know  these  drugs  have  no  chemical  affinity  for  each 
other;  both  are  alkaloids,  yet  they  produce  exactly  opposite  effects 
on  the  eye,  salivary  glands,  heart,  intestine,  etc. 

The  antagonism  in  this  case,  as  in  most  cases,  is  not  mutual,  i.  e., 
the  action  of  one  drug  is  not  equal  and  opposite  to  the  action  of  the 
other.  Small  doses  of  atropin  will  counteract  the  effects  of  large 
doses  of  pilocarpin,  but  pilocarpin  is  not  antagonistic  to  large 
doses  of  atropin.  In  this  as  in  m.ost  cases  the  paralyzing  drug  is 
much  stronger  than  the  stimulating  drug. 

The  antagonism  may  be  explained  in  this  case  by  assuming  that 
these  drugs  act  on  the  same  place:  the  myoneural  junctions,  one 
stimulating,  the  other  depressing.  When  the  ending  is  paralyzed 
by  atropin,  of  course,  no  further  acticm  can  be  expected,  since 
paralysis  requires  a  i)eriod  of  recuperation  before  the  ending  is 
again  rcsjxmsive  to  any  stimulus. 

On  striix'd  muscle,  curara  i)aralyzes  the  nerve-endings;  eserin 
here  is  antagonistic,  but  the  degree  of  the  antagonism  is  again 
limited.  The  effect  of  curara  soon  wears  off,  but  eserin  facilitates 
the  r(!Cuperation  and  actually  stimulates  the  endings. 


164  ANTAGONISM 

In  the  case  of  veratrin,  which  acts  directly  on  muscle  and  stimu- 
lates it,  potassium  chloride  and  fatigue  products  are  antagonistic, 
and  again  the  paralyzing  drugs  are  stronger  than  the  stimulating. 

Barium  and  the  nitrites  are  antagonistic  on  muscle,  but  we  do 
not  know  whether  they  act  on  the  same  substance  in  the  muscle. 

Barium,  veratrin  and  digitalis  increase  the  force  of  contraction  of 
the  heart  while  chloroform,  chloral  and  potassium  salts  diminish  it. 
In  this  and  in  many  other  cases  of  antagonism  it  is  difficult  to  analyze 
the  mechanism  because  there  are  so  many  possible  factors.  It  is 
not  at  all  necessary  that  antagonistic  drugs  act  on  the  same  point, 
since  the  reciprocal  nerves  in  many  organs  are  antagonistic  in  their 
physiological  effect,  as  has  already  been  pointed  out. 

HCN,  CH3,  CN,  and  other  nitrils,  in  the  presence  of  active 
sulphur  compounds,  are  converted  into  less  toxic  sulphocyanides. 
They  also  retard  or  modify  the  power  of  the  body  to  break  down 
substances  which  in  themselves  are  not  toxic,  yet  their  decom- 
position products  are  toxic.  Hunt's  acetonitril  test  illustrates  this 
type  of  antagonism. 

Hunt  found  that  the  administration  of  thyroid  gland  extract  to 
white  mice  for  a  few  days  markedly  increases  their  resistance  to 
an  acetonitril.  He  found  that  after  thyroid  feeding,  acetonitril, 
which  is  toxic,  by  being  broken  into  HCN  is  less  toxic  after  feeding 
thyroid.  Certain  foods,  not  well  understood,  may  have  a  similar 
influence,  since  dextrose,  oatmeal,  liver  and  kidney  also  increase 
this  antagonism. 

Little  is  known  regarding  this  type  of  antagonism  or  the  antago- 
nism resulting  from  internal  secretions  or  hormones. 

Epinephrin  sensitizes  sympathetic  nerve-endings.  Cholin  is 
thought  to  sensitize  autonomic  ganglia.  The  chemical  functions 
of  the  liver  are  modified  by  the  amount  of  epinephrin  in  the  blood 
and  also  by  the  condition  of  the  thyroid.  Modifications  of  these  and 
other  fmictions  undoubtedly  synergize  or  antagonize  drug  action, 
but  too  little  is  known  about  such  action  to  give  an  explanation. 

Disease,  climate,  food  and  perhaps  other  conditions  may  antago- 
nize morphin.  In  cold  climates  purgatives  are  less  effective  than 
in  warm.  Many  other  unknown  conditions  may  modify  the  action 
of  drugs. 

Synergism. — Synergism  is  the  opposite  of  antagonism.  The  term 
is  confused  with  additive  action.  In  true  synergism  the  sum  of  the 
influence  of  two  drugs  is  more  than  the  addition  reaction  of  the  two. 
There  is  a  sensitizing  action  by  one  of  them,  so  that  the  other  pro- 
duces more  than  its  normal  action.    For  example: 


PHYSIOLOGICAL  ANTAGONISM  165 

1.  A  mLxture  of  purgatives  increases  the  activity  of  both. 

2.  ]Morphin  and  chloral  and 

3.  Morphin  and  scopolamin  as  h^-pnotics. 

4.  ^Mercury  and  arsenic  in  syphiUs. 

No  explanation  of  synergism  is  at  present  available. 

Scopolamin,  Morphin,  Synergism} — In  the  following  experi- 
ments record  respiration  and  heart-rate,  corneal  reflex  and  general 
appearance  and  condition  of  animals  before  and  during  the  experi- 
ment. 

Experiment  I. — Give  a  rabbit  0.03  gram  of  morphin  per  kilo 
subcutaneously  and  observe  and  record  the  effect  for  one  hour. 

Experiment  H. — Give  a  rabbit  0.02  gram  per  kilo  (1  c.c.  of  2  per 
cent.)  scopolamin  subcutaneously  and  observe  and  record  the  effect 
for  one  hour. 

Experiment  m, — Give  a  rabbit  0.04  gram  of  morphin  per  kilo 
(1  c.c,  4  per  cent.)  subcutaneously  and  observe  and  record  the 
effect  for  one  hour. 

Experiment  IV. — Give  a  rabbit  0.03  gram  of  morphin  per  kilo 
(1  c.c,  3  per  cent.)  and  0.01  gram  per  kilo  (1  c.c,  1  per  cent.)  sco- 
polamin and  observe  and  record  the  effect  for  one  hour.  Compare 
the  results  of  these  four  experiments. 

Experiment  V. — Give  a  rabbit  0.01  gram  of  morphin  and  0.01 
gram  of  scopolamin  (1  c.c,  1  per  cent.)  per  kilo  and  observe  for  one 
hour. 

Experiment  VI. — Select  two  cats  the  same  size,  (a)  Give  one  as 
a  control  0.05  gram  of  morphin  (1  c.c,  5  per  cent,  or  equivalent) 
and  notice  the  effect  after  thirty  minutes. 

(6)  Give  the  second  animal  0.1 00  gram  of  narcotin  subcutaneously. 
Note  the  influence  of  this  for  one  hour.  Then  give  the  same  amount 
of  morphin  (0.05  gram)  as  the  control  and  observe  for  one  hour. 

ic)  Take  A  and  after  one  and  a  half  hours  give  the  same  dose  of 
narcotin  as  B  (0.100  gram)  and  compare  the  two  animals.^ 

Experiment  Vn. — Synergism  oj  Morphin  and  Paparerin. — Repeat 
Experiment  VI,  using  papaverin  instead  of  narcotin. 

Experiment  Vm.  —  Synergism  of  Morphin,  Scopolamin  and 
Atropin. — Take  five  cats.  Inject  three  cats  each  with  25  mg.  per 
kilo  of  morphin  subcutaneously. 

1.  Use  as  a  control. 

2.  Give  the  second  animal  1  c.c.  of  0.1  per  cent.  scoi)()lamin 
hypfnlermically. 

•  Madclung:  Arch,  of  Exp.  Path.  u.  Pharm.,  1910,  Ixii,  422. 
«  Straub:  Hiochomischc  ZtHf:hr.,  1912,  xli,  4.'/J. 


166  ANTAGONISM 

3.  Give  this  animal  1  c.c.  of  0.01  per  cent,  atropin. 

4.  Give  1  c.c.  of  0.1  per  cent,  scopolamin  as  control. 

5.  Give  1  c.c.  of  0.1  per  cent,  atropin  as  control. 
Compare  and  record  results. 

Scopolamin  and  urethane  are  also  synergistic/  also  morphin  and 
urethane.  The  narcotic  dose  of  urethane  for  a  rabbit  is  1.5  gram 
per  kilo  by  mouth  or  1  gram  per  kilo  subcutaneously. 

Experiment  IX. — Give  two  rabbits  each  0.1  gram  per  kilo  of 
scopolamin  subcutaneously.  Save  one  for  control.  Give  the  other 
0.2  gram  per  kilo  urethane  subcutaneously.  To  a  third  give  1 
gram  per  kilo  urethane  by  stomach  tube. 

Experiment  X. — Give  two  rabbits  0.2  gram  per  kilo  of  urethane 
subcutaneously.  Save  one  for  control.  Give  the  other  0.1  gram 
per  kilo  of  scopolamin.  Compare  the  results  of  this  in  both  experi- 
ments. 

In  the  same  way  Burgi  has  found  that  the  antipyretics  have  some 
anesthetic  action  and  increase  the  action  of  morphin  and  urethane. 

EXAMINE  AND  STUDY  THE  VARIOUS  PREPARATIONS  IN 
WHICH  EPINEPHRIN  IS  FOUND  IN  THE  MARKET. 

Experiment  I. — 1.  Prepare  a  dog  or  cat  for  blood-pressure  and 
respiration  tracings.  Note  the  condition  of  the  pupil  before  and 
after  each  injection.  Insert  a  cannula  into  the  femoral  vein  for 
intravenous  injections  from  a  burette.  Make  an  incision  along  the 
linea  alba,  about  four  inches  long,  and  observe  the  condition  of  the 
intestine  during  each  injection.  Keep  the  part  warm  and  closed 
when  not  under  observation.  Take  three  samples  of  the  blood  and 
determine  clotting  time. 

2.  Take  normal  tracings,  then  tracings  of  the  action  of  1  c.c.  of 
1  to  10,000  epinephrin  subcutaneously. 

3.  After  five  minutes  inject  1  to  50,000  epinephrin  intravenously; 
when  pressure  is  high  stimulate  the  vagus,  compare  with  stimula- 
tion when  the  pressure  is  normal. 

4.  Isolate  and  cut  one  vagus  and  again  inject  1  to  10,000  epi- 
nephrin. 

5.  Isolate  and  cut  the  other  vagus  and  inject  1  to  10,000  epi- 
nephrin. Is  there  any  change  in  the  height  or  character  of  the  curve 
after  cutting  the  vagi?  Is  there  a  secondary  rise  in  the  pressure 
following  a  primary  fall?    If  so  how  do  you  explain  it? 

1  Burgi:  Deut.  Med.  Wchschr.,  1910,  pp.  20  and  62, 


PREPARATIONS  IN   WHICH  EPINEPHRIN  IS  FOUND     167 

6.  When  the  pressure  is  again  normal,  stimulate  the  peripheral 
vagus. 

7.  Take  the  clotting  time  of  the  blood  and  compare  with  the 
normal. 

8.  Inject  intravenously  2  c.c.  of  pituitrin  (liquor  hypophysis), 
1  to  5  in  water.    Compare  this  action  with  the  action  of  epinephrin. 

9.  When  the  pressure  is  again  normal  inject  double  the  amount 
of  pituitrin  (liquor  hypophysis)  subcutaneously.  Note  effects  for 
thirty  minutes. 

10.  At  this  stage  inject  1  c.c.  of  1  per  cent,  atropin  sulphate 
solution.  What  is  the  effect  on  the  heart,  respiration  and  eye? 
Study  the  changes  in  the  tracings  under  the  various  drugs. 

Experiment  11. — Prepare  for  tracings  as  in  Experiment  I.  Watch 
the  effects  on  the  pupils,  heart,  respiration,  intestine  and  salivary 
flow.    Determine  the  clotting  time  of  the  blood. 

1.  Inject  2  c.c.  of  1  to  5  solution  of  pituitrin  (liquor  hypophysis) 
intravenously.  Wait  until  the  pressure  has  returned  to  normal. 
Determine  clotting  time.    Then — 

2.  Inject  1  c.c.  of  1  to  10,000  epinephrin.  When  pressure  is 
again  normal — 

3.  Inject  1  c.c.  of  1  per  cent,  atropin  sulphate,  in  five  minutes — 

4.  Inject  1  c.c.  of  1  to  10,000  epinephrin  and  compare  the  result 
with  2  to  5,  Experiment  I.    Determine  clotting  time  again. 

0.  Expose  the  intestines  to  produce  a  condition  of  shock  and 
when  the  blood-pressure  has  been  much  reduced,  again  inject  1  c.c. 
of  1  to  10,000  epinephrin. 

Experiment  HI. — Action  of  Epinephrin  on  Vasodilators. — Prepare 
for  tracings  as  in  Experiment  I  and  11. 

1.  Take  normal  tracing. 

2.  Inject  intravenously  \  c.c.  per  kilo  of  1  to  100,000  epinephrin 
solution.  Repeat  this  and  vary  the  dose  and  see  if  you  can  get  a 
dose  that  will  give  a  fall  only.  Note  that  a  slight  rise  may  be  fol- 
lowed by  a  fall  and  again  by  a  secondary  rise.  How  do  you  account 
for  this? 

3.  Inject  slowly  j\  c.c.  per  kilo  of  the  fluidextract  of  ergot. 

4.  Refxjat  (2). 

5.  Repeat  (3). 
0.  Repeat  (2). 

Instead  of  ergot,  ergotoxin  may  be  used  if  it  is  available.  Pre- 
pare a  solution  of  ergotoxin  as  follows:  Weigh  out  0.1  gram  and  place 
in  a  beaker.  Moisten  with  10  per  cent.  XaOII.  Add  water  slowly, 
and  about  1  c.c.  at  a  time,  until  the  powder  is  dissolved.    Make 


168 


ANTAGONISM 


to  20  c.c.    This  is   0.5  per  cent.,  and  1    c.c.  equals  0.005  gram. 
Ergotoxin  paralyzes  the  vasoconstrictors  before  the  dilators. 

Experiment  IV. —  The  Action  of  Epinephrin  on  the  Intestine. — 
Anesthetize  the  animal  and  prepare  for  recording  the  intestinal 
movements  by  the  Trendelenburg  method  or  by  Jackson's  finger- 
cot  method. 


Fig.  39. — Jackson's  finger-cot  method  of  recording  intestinal  contraction. 


1.  Trendelenburg's  method  as  described  by  Dr.  R.  G.  Hoskins: 
Use  a  dog  that  has  been  one  day  without  food.  Insert  a  tracheal 
cannula  and  attach  to  an  ether  bottle  (see  Fig.  17,  page  86.) 

Pith  the  Dorsal  Spinal  Cord  in  the  Following  Manner:  Cut  down 
to  the  laminse  of  the  first  and  second  lumbar  vertebrae,  detaching 
the  muscles  from  the  spinous  processes.  With  bone  forceps  remove 
these  processes  and  laminse  (controlling  hemorrhages  with  pledgets 
of  cotton  saturated  with  ferric  sulphate  solution,  5  per  cent.), 
exposing  the  spinal  cord.  With  rotary  motion  insert  anteriorly  a 
soft  wire,  with  the  end  recurved,  to  form  an  open  hook  about  4  or  5 
mm.  across.  Remove  the  wire.  Insert  a  cotton  pledget  and  close  the 
incision. 

2.  Prepare  gut  for  tracing  as  follows:  Make  an  opening  in  the 
abdominal   wall   along   the   linea   alba   and   sew  in  an   iron  ring 


PREPARATIONS  IN   WHICH  EPINEPHRIN  IS  FOUND     169 

about  14  cm.  in  diameter.  Fasten  the  ring  to  a  stand  and  fill 
the  abdominal  cavity  with  Ringer's  solution  at  body  temperature. 
Avoid  all  rough  handling.  Pass  a  guide  ligature  around  the  gut  (to 
be  used  for  drawing  the  gut  up  when  injections  are  to  be  made  into 
it);  and  25  to  30  cm.  below  it,  by  means  of  a  small  surgical  needle 
pass  a  silk  thread,  fifteen  inches  long,  in  a  transverse  direction 
through  the  superficial  layer  of  the  gut,  and  after  tying  pass  the 
end  through  the  glass  cylinder  (finger  plethysmograph) .  One-half 
inch  above  this  thread  sew  a  single  superficial  stitch.  Sew  the 
opposite  end  of  the  cylinder  to  the  gut  a  half-inch  below  in  the  same 
way.  Fix  the  cylinder  perpendicularly  in  a  burette  clamp  and 
attach  the  long  thread  to  a  heart  lever  arranged  to  magnify 
seven  times  and  to  write  on  a  kymograph  drum.  (The  cylinder 
decreases  the  displacement  of  the  gut  respiratory  movements.) 

3.  Arrange  for  injections  into  the  femoral  vein  from  a  burette. 
It  usually  requires  thirty  to  sixty  minutes  for  good  contractions  to 
commence. 

Experiment  V. — Jackson's  Finger-cot  Method. — Arrange  a  burette, 
catheter  and  finger-cot  or  rubber  glove  finger  as  shown  (Fig.  39), 
and  make  a  small  longitudinal  incision  in  a  loop  of  the  small  intestine. 
Slip  the  end  of  the  catheter  over  which  the  finger  cot  is  attached  about 
four  or  five  inches  down  the  lumen  of  the  intestine  from  the  incision. 
(The  tip  of  the  catheter  reaches  entirely  to  the  end  of  the  finger  cot 
and  thus  forces  the  cot  along.)  Fill  the  burette  half-full  of  water 
and  move  the  catheter  in  and  out  a  little  to  be  sure  that  the  finger 
cot  is  filled  with  water  and  the  air  is  expelled.  Stitch  together  the 
incision  in  the  intestine  around  the  catheter  and  close  the  abdomen 
with  hemostats.  The  intestinal  tambour  should  write  just  above 
the  blood-pressure,  respiration  and  base  line. 

Experiment  VI. — Action  of  Epinephrin  on  the  Uterus. — (a)  Remove 
the  uterus  of  a  guinea-pig,  rabbit  or  cat.  Place  in  a  warm  saline 
solution.  Take  a  piece  of  one  horn,  about  one-half  inch  long,  and 
set  up  as  for  muscle  contractions  in  a  warm  saline  bath  (Fig.  37). 
Keep  oxygen  or  air  bubbling  through  the  immersing  fluid.  When 
contractions  are  regular  add  a  drop  or  two  of  1  to  1000  epinephrin 
solution . 

(6)  Remove  and  add  saline  again.  When  contractions  are  again 
regular  adrj  1  c.c,  of  1  to  10  pituitrin. 

(c)  Iicmove  the  pituitrin  fluid  and  i)hysiological  saline.  When 
contractions  are  regular  add 

(d)  1  c.c.  of  1  to  10  fluidextract  of  ergot.  Other  drugs  may  be 
tried  as  desired. 


170  ANTAGONISM 

Experiment  VII. — Barbour's  Method  of  Studying  the  Action  of  Drugs 
on  the  Uterus.^ — Get  this  journal  and  read  the  article.  Barbour's 
method  of  recording  uterine  contractions  is  much  like  the  Trendelen- 
burg method  for  intestinal  movements.  An  opening  is  made  in  the 
linea  alba  and  the  horns  of  the  uterus  loosened  and  brought  forward 
together  and  a  thread  tied  around  the  ends  of  both.  Now  place  a 
glass  tube,  like  a  finger  plethysmograph,  perpendicular  in  the 
abdomen,  so  that  it  contains  the  uterus  and  protects  it  from  the 
other  abdominal  organs.  Bring  the  thread  that  is  around  the  uterine 
horns  through  the  tube  and  attach  to  a  light  writing  lever.  .  Fill 
the  abdomen  with  liquid  paraffin  for  protection  and  sew  the  skin  of 
the  abdomen  around  the  tube.  Inject  the  drugs  to  be  studied  into 
the  femoral  veia.  This  method  should  give  a  more  accurate  indica- 
tion of  drugs  on  the  uterus  than  a  method  that  applies  the  drugs 
directly  to  the  uterus,  a  form  in  which  they  never  reach  it  when 
given  therapeutically.    Cats  are  the  best  animals  for  this  work. 

Experiment  VIII. —  The  Action  on  the  Eye. — (a)  The  eye  should 
have  been  observed  in  all  the  foregoing  experiments. 

(b)  Take  the  eyes  of  a  frog  and  place  them,  one  in  saline,  0.8 
per  cent.,  the  other  in  saline  containing  1  to  10,000  epinephrin. 
Place  in  a  dark  place  and  observe  every  fifteen  minutes.  What  is 
the  result?  Why  does  this  occur  in  the  dark  more  easily  than  in 
daylight? 

Experiment  IX. —  The  Action  of  Epinephrin  on  the  Secretions. — (a) 
Anesthetize  a  dog  and  place  a  cannula  in  Wharton's  duct  and  prepare 
for  blood-pressure  tracings,  stimulation  of  the  chorda  tympanum 
and  cervical  sympathetics.  Take  normal  tracing  and  record  of 
blood-pressure  and  salivary  flow.  Stimulate  the  chorda  and  sym- 
pathetic separately.  Note  the  results.  If  the  sympathetic  cannot 
be  conveniently  isolated  proceed  without  it. 

(6)  Inject  1  c.c.  of  1  to  10,000  epinephrin  and  note  the  effect  on 
the  salivary  flow.    Repeat. 

(c)  Inject  epinephrin.  When  satisfied  with  the  action  of  epi- 
nephrin on  the  secretion  again  stimulate  the  chorda. 

(d)  Inject  intravenously  1  c.c.  of  1  per  cent,  atropin  sulphate  and 
in  five  minutes  repeat  stimulation  of  the  chorda. 

(e)  When  the  stimulation  of  the  chorda  is  ineffective  repeat  injec- 
tions of  epinephrin  1  to  10,000  and  note  results.  If  the  sympathetics 
have  been  isolated  stimulate  directly. 

1  Journal  of  Pharm.  and  Exp.  Ther.,  1915,  vii,  547. 


PREPARATIONS  IN  WHICH  EPINEPHRIN  IS  FOUND     171 

Experiment  X. — Glycosuria  Produced  by  the  Hypodermic  Injection 
of  Epinephrin. — Catheterize  a  rabbit  and  test  the  urine  for  sugar. 
If  there  is  sugar,  inject  1  c.c.  per  kilo  of  1  to  10,000  epinephrin 
subcutaneously.  In  two  to  three  hours  catheterize  and  again  test 
the  urine  for  sugar.    The  test  rarely  fails. 

Experiment  XI. —  The  Action  of  Epinephrin  on  theTone  of  Bronchial 
Muscle. — The  bronchial  muscles  are  acted  on  by  drugs  that  act  on 
non-striated  muscle.  They  are  relaxed  by  atropin  and  constricted 
by  drugs  of  the  pilocarpin-eserin  group,  etc.  Elimination  of  the 
indirect  action  of  the  drug  on  respiration  and  vasomotor  apparatus 
makes  the  measurement  of  the  bronchial  tone  rather  difficult.  Care 
must  be  taken  to  avoid  an  action  on  the  respiratory  center  being  in- 
terpreted as  an  action  on  the  bronchial  muscles.  For  this  reason  the 
animal  is  pithed  and  artificial  respiration  is  carried  out.  Changes 
in  the  blood  flow  through  the  lungs  must  also  be  accounted  and  not 
confused  with  bronchial  changes.  Methods  have  been  developed  by 
Dixon  and  Brodie/  Golla  and  Symes,^  and  D.  E.  Jackson.^  The 
method  is  essentially  as  follows: 

Anesthetize  a  dog  and  insert  a  three-way  tracheal  cannula 
for  artificial  respiration.  Isolate  the  carotid  arteries  and  ligate 
one.  With  a  large  needle  pass  ligatures  through  all  the  muscles  of 
the  neck  close  to  the  vertebra  so  that  the  entire  return  circulation 
from  the  head  can  be  shut  off.  When  ready  to  do  this  inject  2  c.c. 
of  chloroform  into  the  central  end  of  the  carotid.  This  will  kill  the 
brain  and  has  the  effect  of  pithing.  Commence  artificial  respiration 
at  once.  This  method  will  kill  the  animal  if  enough  chloroform 
reaches  the  heart.  It  is  important,  therefore,  that  as  soon  as  injec- 
tions of  chloroform  are  made  ligation  of  the  return  vessels  be  made 
at  once. 

A  safer  method  of  pithing  is  to  open  the  skull  with  a  trephin  and 
pith  with  an  iron  rod.  Pack  tightly  with  cotton  to  avoid  hemor- 
rhage. Pithing  should  be  sufficiently  low  to  destroy  the  respiratory 
center.  The  simplest  method  of  pithing  is  to  inject  1  c.c.  of  CHCI3 
into  the  fourth  ventricle.  This  will  also  destroy  the  respii*atory 
centre,  so  that  artificial  respiration  should  be  established  as  soon 
as  the  injection  is  made.'' 

Insert  a  cannula  into  the  jugular  or  femoral  vein  for  injection. 
Shave  the  chest  on  one  side  near  the  diaphragm  and  insert  a  flanged 

'  Jour.  Physi'ol.,  190.3    xxix,  97. 

2  .Jcur.  Pharmacol.,  1914,  v,  92. 

'  Ibid.,  iv  and  v;  also  Expcr.  Pharrn.  Text  horjk,  1017. 

*  .lour,  f'f  Lab.  and  Chcm.  Med.,  1919,  iv,  491. 


172  ANTAGONISM 

cannula  into  the  pleura.  The  opening  or  incision  around  the  cannula 
must  be  air-tight.  A  little  collodion  around  the  incision  will  help. 
Connect  with  a  tambour  or  water  manometer  and  make  a  tracing 
of  the  pulmonary  excursions.  Keep  the  respiration  regular.  If  the 
blood  volume  in  the  lungs  remains  constant  and  the  artificial 
respiration  is  regular  an  increase  or  decrease  in  the  excursions  of 
the  tambour  is  assumed  to  be  due  to  changes  in  the  bronchial 
muscles.     Criticize  this  assumption. 

1.  Study  the  effect  of  the  intravenous  injection  of  1  c.c.  of  1  to 
10,000  epinephrin. 

2.  1  c.c.  of  0.1  per  cent,  pilocarpin. 

3.  1  to  10,000  epinephrin. 

4.  1  c.c.  of  pilocarpin,  1  per  cent.    . 

5.  1  c.c.  of  0.5  per  cent,  atropin  sulphate. 

6.  Repeat  1. 

7.  1  c.c.  of  1  to  5  pituitrin. 

8.  Before  killing  the  animal  inject  1  c.c.  of  1  per  cent,  barium 
chloride. 

Note  to  student:  Criticize  the  technic  and  conclusions  of  this 
experiment.  Wherein  may  the  results  not  indicate  an  action  on 
the  bronchioles? 


CHAPTER  XV. 

ANTIPYRESIS  AND  ANTIPYRETICS. 

In  the  normal  animal  heat  production  and  heat  loss  are  main- 
tained at  a  constant  level — the  normal  body  temperature.  The 
normal  temperature  of  different  animals  is  as  follows:^ 


Birc 

Is. 

^ 

[ammals. 

Goose    . 

.      .      41.70°  C. 

Tiger      .      . 

.      .      37.20°  C. 

/  39.08°  C. 

/  36.80° C 
■      •      ■  \  37.50°  C 

Sparrow 

•      ■\42.10°C. 

H  orse     . 

Pigeon   . 

/  41.80°  C. 

Rat  .      .      . 

.      .      38.50°  C. 

•      •\42.50°C. 

Hare 

.      .      37.80°  C 

Turkey        .      . 

.      .      42.70°  C. 

Cat  .      .      . 

/  38.30° C 
•      •  \  38.90°  C 

Guinea  fowl 

.      .      43.90°  C. 

Duck     .      .      . 

/  43.90° C. 
•      ■  \  42.50°  C. 

Guinea-pig 

.      .      38.80°  C. 

f 37.40°  C 

Crow 

.      .      41.17°C. 

Dog        .       . 

.      .      39.00°  C 

Swallow 

.      .       44.03°  C. 

[  39.60°  C 

Gull        .      .      . 

.      .      37.80°  C. 

Panther 

.      .      38.90° C 

Mouse    . 

.      .      41.10°  C 

Sheep     . 

/  37.30°  C 
■      ■  \  40.50°  C 

Ape 

.      .      35.50°  C 

Guinea-pig 

/  35.76°  C 
•      •      •  1  38.00°  C 

Rabbit  .      . 

/  37.50°  C 
\  38.00°  C 

Ox    .      .      . 

.      .      37.50° C 

Ass   . 

.      .      36.95°  C 

Anything  that  increases  heat  loss  or  lessens  heat  production  will 
lower  the  temperature.  This  is  regulated  by  the  central  nervous 
system.  Heat  output  is  lessened  reflexly  by  constriction  of  the 
cutaneous  vessels  and  heat  loss  increased  in  the  same  way  by 
vasodilationa  nd  by  sweating. 

The  heat-regulating  center  is  "set"  so  that  shivering  (to  increase 
heat  production)  or  sweating  (to  increase  heat  loss)  occurs  with  a 
slight  change  in  the  temperature. 

A  normal  dog,  with  a  temperature  of  38.6°  C,  will  shiver  when 
the  temperature  is  lowered  0.7°  C,  and  perspire,  i.  e.,  show  the 
signs  of  perspiration,  when  the  temperature  is  raised  0.5°  C,  Our 
knowledge  of  the  location  and  mechanism  of  the  heat-regulating 

>  Landois  and  Stirling,  1891,  p.  406. 


174  ANTIPYRESIS  AND  ANTIPYRETICS 

center  or  centers  is  still  very  incomplete.  However,  toxins,  cocain 
and  other  pyrogenous  poisons  will  derange  the  regulating  center, 
and,  depending  on  the  infection  or  drug,  the  regulating  mechanism 
instead  of  being  set  at  38.6°  C.  may  be  set  at  40°  C.  or  higher. 

The  sensitivity  of  the  center  to  heat  and  cold  at  this  higher  tem- 
perature is  the  same  as  at  the  lower. 

The  reaction  to  cold  probably  means  an  augmented  state  of 
excitability  or  stimulation  of  the  heat-regulating  centers,  while 
increase  in  temperature  depresses  them.  Overheating  of  the  carotid 
blood  is  known  to  depress  the  medullary  centers,  while  at  the  same 
time  the  cooperative  or  reciprocal  centers,  sweat-glands  and  the 
respiration  center  (heat  dyspnea)  may  be  stimulated. 

Fever  is  thought  to  be  due  to  a  stimulation  of  the  heat-regulating 
centers  by  toxins  and  pyrogenous  poisons.  Heat  puncture  also 
stimulates  these  centers  in  the  same  way.  The  mechanism  of  anti- 
pyresis  is  not  well  understood,  but  the  coal-tar  antipyretics  reduce 
the  temperature  in  hyperpyrexia  by  a  sedation  or  depressing  action 
on  the  heat-regulating  mechanism  by  "setting"  the  temperature 
mechanism  at  a  lower  state  as  one  sets  a  thermostat  in  the  laboratory. 

In  fever  the  nitrogen  eliminated  as  urea  and  oxygen  consumed  is 
lessened  by  antipyretics,  but  this  is  a  result  rather  than  the  cause 
of  the  fall  of  temperature,  because: 

1.  No  such  result  occurs  in  the  normal  individual. 

2.  The  excessive  excretion  of  urea  does  not  run  parallel  with  the 
increase  of  temperature  but  is  generally  most  marked  after  the  crisis. 

3.  In  fever  produced  by  the  injection  of  bacterial  toxins,  increase 
in  oxygen  consumption  and  urea  excretion  occurs  even  when  the 
rise  of  temperature  is  prevented. 

ANTIPYRETICS. 

The  immediate  active  agent  in  the  coal-tar  antipyretics  is  para- 
amidophenol,  and  if  this  formed  too  rapidly,  collapse  may  follow. 
Hence  only  those  that  yield  para-amidophenol  slowly  can  be  used. 

These  coal-tar  antipyretics  act  on  the  heat-regulating  center  to 
depress  it,  but  the  actual  reduction  of  temperature  is  due  to  heat 
loss  from  the  surface  of  the  body.  If  the  fevered  animal  be  wrapped 
in  a  cotton  blanket  or  placed  in  an  incubator,  so  that  no  loss  from 
the  surface  can  take  place,  antipyrin  has  little  effect. 

Antipyrin  differs  from  a  cold  bath  in  lowering  the  temperature 
by  the  fact  that  it  has  a  central  action  and  tends  to  permanently 
lower  the  temperature.    That  it  acts  on  the  heat  centers  in  the  brain 


ANTIPYRETICS  175 

is  sho^^^l  by  the  fact  that  high  section  of  the  cord  prevents  its  action 
and  it  has  no  local  or  general  action  as  has  quinin,  while  after  a 
cold  bath  the  tendency  is  for  the  temperature  again  to  rise,  due  to 
increased  heat  formation.  A  cold  bath  does  not  at  least  immediately 
"set"  the  regulating  mechanism.  Alcohol  and  the  nitrites  dilate 
the  superficial  vessels,  but  do  not  set  the  center.  Quinin  lessens 
temperature  by  decreasing  oxidation  in  the  muscles  and  gland  cells. 
The  temperature  fall  is  secondary  to  diminished  metabolism. 
Quinin  inhibits  oxidation  by  oxidases  in  vitro,  and  it  reduces  the 
temperature  of  the  normal  animal.  The  action  is  not  on  the  brain, 
since  it  reduces  the  temperature  of  an  animal  whose  cord  is  cut. 
The  coaltar  antipyretics  will  not  act  if  the  cord  is  cut. 

Experiment  I. — ia)  Take  the  rectal  temperature  of  eight  rabbits. 

(6)  Give  each  a  hypodermic  injection  of  2  c.c.  of  5  per  cent, 
cocain  per  kilo. 

(c)  Record  the  temperature  each  fifteen  minutes  until  a  maximum 
is  obtained ;   then  give — 

1.  Two  c.c.  of  2  per  cent,  solution  of  a  quinin  salt;  repeat  every 
fifteen  minutes  until  the  temperature  falls. 

2.  Wrap  in  cotton  and  treat  the  same  as  in  1. 

3.  Give  an  injection  of  5  c.c.  per  kilo  of  2  per  cent,  acetanilid  in 
alcohol. 

4.  Treat  the  same  as  in  3.  First  wrap  in  cotton;  repeat  every 
fifteen  minutes  until  the  temperature  falls. 

.5.  Immerse  in  a  water-bath  at  25°  C, 

6.  Immerse  in  a  water-bath  at  40°  C. 

7.  Give  by  mouth  10  c.c.  per  kilo  of  2  per  cent,  acetanilid  solution 
in  alcohol. 

8.  Give  10  c.c.  per  kilo  of  2  per  cent,  antipyrin  by  mouth. 
Make  complete  records  and  discuss  the  mode  of  action  of  each 

of  these  drugs. 

As  a  control,  if  sufficient  animals'  are  available,  treat  eight  other 
rabbits  in  the  same  way  without  giving  the  cocain. 

Experiment  II. — Take  the  temperature  of  eight  rabbits  and  inject 
hypodermically  with  1  c.c.  per  kilo  of  })ody  weight  of  20  per  cent, 
peptone  in  water  twelve  hours  before  class  work.  Then  treat  as 
in  Experiment  I. 

Experiment  HI. Take  the  normal  tem])erature  and  note  the 
chaiig<-s  produced  in  the  following  experiments: 

Ilydruted  Chloral. — Administer  ().))  gram  of  iiN'dratcd  ciiloral  to 
a  cat  (0.0  gram  to  a  rabbit;  by  the  rcctiini.  Note  the  degree  of 
anesthesia  induced. 


176  ANTIPYRESIS  AND  ANTIPYRETICS 

Morphin. — Administer  100  mg.  of  morphin  sulphate  (3  c.c.  of 
3  per  cent,  solution)  per  kilo  to  a  rabbit  subcutaneously  (half  of  the 
relative  amount  to  a  dog) ;  compare  the  anesthetic  action  with  that 
of  hydra  ted  chloral.  The  temperature  of  a  dog  may  or  may  not  fall; 
that  of  a  rabbit  falls. 

Antipyrin  in  Health. — Administer  100  mg.  of  antipyrin  to  a  normal 
rabbit  through  a  stomach-tube;  little  change  in  temperature. 
Note  that  the  temperature  of  rabbits  undergoes  marked  changes, 
with  changes  in  external  temperature,  with  careless  handling,  fright 
or  excitement;  hence  the  success  of  these  experiments  demands 
careful  work. 

Experiment  IV. — ^Each  student  should  record  his  own  temperature 
and  take  0.5  gram  of  antipyrin  or  other  antipyretic.  Record  the 
temperature  every  hour  for  four  hours. 

Experiment  V. — Record  the  temperature  and  respiration  of  four 
rabbits.  Place  in  an  adequately  ventilated  box  and  raise  the  tem- 
perature in  the  box  to  43°  C.  by  means  of  an  electric  light  within 
the  box.  In  two  hours  record  the  temperature  again.  Give  two 
10  c.c.  per  kilo  of  2  per  ceat.  antipyrin  by  mouth  and  replace  in  the 
heated  box ;  allow  the  otheT  two  to  remain  at  the  room  temperature 
without  antipyrin.  At  the  end  of  an  hour  again  record  the  tempera- 
ture and  respiration.  Discuss  the  hygienic  and  drug  treatment  of 
fever. 

Experiment  VI. — Heat  Centers. — Demonstration.- — Puncture  of  the 
median  part  of  the  corpus  striatum  and  other  parts  of  the  nervous 
system  often  causes  a  rise  in  temperature.  The  centers  are  not 
definitely  localized.  It  has  been  suggested  that  the  rise  in  tem- 
perature in  fevers  is  due  to  bacterial  toxins  acting  on  these  centers 
and  that  antipyretics  restore  these  centers  to  their  normal  state 
either  by  preventing  the  formation  of  these  toxins,  neutralizing 
them  or  causing  their  more  rapid  elimination.  Study  the  mechanism 
of  each  antipyretic  in  the  text. 

Experiment  VII. — 1.  Record  rectal  temperature  of  two  rabbits: 
Into  one  inject  intravenously  1  to  1.5  c.c.  per  kilo  fluidextract  of 
ergot  and  record  the  temperature  every  thirty  minutes. 

2.  Into  two,  inject  in  same  way  5  to  8  c.c.  of  1  to  20  solution  of 
calcium  lactate  and  record  temperature  in  the  same  way.^ 

Experiment  VIII. — ^Record  the  blood-pressure  and  respiration  of  a 
dog.  Lay  bare  the  carotid  and  place  it  on  a  copper  jacket  so  con- 
structed that  a  stream  of  hot  water  may  be  circulated  around  the 

1  See  Hill:     Jour,  of  Pharm.  and  Exp.  Therap. 


ANTIPYRETICS  177 

carotid  artery  as  it  passes  to  the  brain.    What  is  the  effect  on  the 
heart  and  respiration? 

Experiment  IX.— Anesthetize  a  cat  or  rabbit  with  ether.  Prepare  for 
aseptic  operation.  ISIake  central  incision  in  the  skin  of  head  along  the 
sagittal  suture.  Peel  back  the  skin  and  make  a  trephine  hole  5  mm. 
lateral  to  the  sagittal  suture  and  the  same  distance  anterior  to  the 
coronal  suture.  When  the  bone  is  removed,  pmicture  with  a  hat- 
pm  or  small  probe,  directed  downward  until  it  touches  the  base  of 
the  skull,  and  is  twisted  around  in  this  location.  Watch  the  con- 
dition of  the  ear  vessels.  Close  the  operative  wound  aseptically, 
remove  the  ether  and  record  the  rectal  temperature  every  fifteen 
minutes  for  three  hours  or  more.^ 

I  See  Prince  and  Hahn:  Am.  Jour.  Physiol.,  1918,  xlvi,  412.  This  gives  refer- 
ences to  other  literature,  aho  Gottlieb,  Arch.  Expt.  Path.  u.  Pharm  1890  xxvi 
419.  .  •  , 


12 


CHAPTER  XVI. 
PHARMACOLOGY  OF  THE  GLANDS. 

The  word  glands  comes  from  the  Latin  glans — acorn,  referring 
to  the  shape  of  glands  in  general,  (see  Fig.  19,  page  99.) 

The  function  of  glands  is  secretion.  This  may  be  external  or 
internal. 

The  chief  glands  of  external  secretion  are: 

1.  The  Lacrimal. 

2.  Salivary. 

3.  Gastro-intestinal. 

4.  Pancreatic. 

5.  Liver,  bile. 

6.  Kidneys. 

7.  Mammary. 

8.  Sweat  and  sebaceous. 

Glands  of  internal  secretion  (endocrinal) : 
L  Thyroid. 

2.  Thymus. 

3.  Adrenals. 

4.  Liver. 

5.  Spleen. 

6.  Testes  and  ovaries. 

7.  Perhaps  all  glands  and  tissues  to  some  extent. 
Lacrimal  Glands. — ^Function  to  moisten  the  eye. 

The  nerves  of  the  lacrimal  glands  are:  Sympathetic  from  the 
superior  cervical  ganglion.  Parasympathetic  from  the  fifth  nerve 
through  the  lacrimal  nerve. 

Drugs  Affecting  the  Gland. — ^The  atropin  group — paralyzing;  the 
pilocarpin-eserin  group — stimulation ;    epinephrin — stimulating. 

According  to  the  rule,  atropin  paralyzes  the  parasympathetic 
nerve-endings. 

Eserin  and  pilocarpin  stimulate  the  parasympathetic  nerve- 
endings. 

Epinephrin  stimulates  the  sympathetic.  The  gland  may  also  be 
stimulated  reflexly  over  the  parasympathetics  through  the  second 
and  seventh  nerves. 


INTESTINAL  SECRETION  179 

Salivary  Glands. —  Nerves. — Sympathetics  through  the  superior 
cervical  ganglion  and  parasympathetics — through  the  chorda  tym- 
pani,  a  branch  of  the  seventh  cranial. 

Function  of  the  Glands. — To  provide  fluid  to  moisten  the  buccal 
cavity,  the  food,  and  to  secrete  a  digestive  enzyme,  ptyalin. 

The  nerves  also  supply  fibers  to  the  vessels  of  the  gland;  the 
s\Tripathetic  are  constrictors  and  the  parasympathetic  are  dilators. 

Methods  of  Actiiig  on  Glands. — 1.  Directly.  2.  Reflexly:  Taste, 
smell,  movements,  chewing,  acids  and  pungent  tasting  substances. 

Direct  Stiimdation. — 1.  Through  the  Chorda. — Pilocarpin,  eserin, 
muscarin,  cholin. 

2.    Through  the  Sympathetic. — Epinephrin,  cocain. 

Depression. — 3.   Through  the  Chorda. — The  atropin  group. 

Depression. — 4.  Through  the  Sympathetic. — Morphin — central 
action. 

Stimulation  through  action  on  all  ganglion  cells — nicotin,  lobelin. 

Elimination  of  Drugs  by  the  Salivary  Glands. — Drugs  are  excreted 
in  small  amounts  by  the  salivary  glands. 

The  following  have  been  found:  Iodides,  bromides,  hexamethyl- 
enamin,  mercurial  and  lead  compounds,  quinin  and  some  other 
alkaloids,  sulphocyanides. 

Gastric  Secretion. — Function  of  the  gastric  glands — secretion  of 
digestive  and  diluting  fluids. 

Nerves. — The  stomach  receives  both  motor  and  inhibitory  fibers 
from  the  vagus.  The  finer  anatomy  of  these  is  not  known.  It  is 
probable  that  there  are  sympathetic  fibers  mixed  with  the  para- 
sympathetic. The  parasympathetic  are  motor;  the  sympathetic, 
inhibitory. 

The  secretion  of  gastric  juice  is  influenced  by  drugs,  similarly 
to  salivary  secretion,  but  to  a  lesser  degree. 

The  pilocarpin  group  stimulates  secretion.  The  atropin  group 
diminishes  it. 

From  a  practical  standpoint  the  action  of  these  drugs  on  the 
stomach  in  diseased  condition  is  of  little  value,  because  they  act  on 
nerve-endings,  and  in  most  diseases  where  stimulation  is  needed 
the  gland  cell  is  involved  or  destroyed.  In  cases  of  hypersecretion 
the  atropin  grouj)  of  drugs  are  of  value. 

Intestinal  Secretion. — The  secretion  of  intestinal  juice  is  somewhat 
influenced  \)y  mechanical,  chemical  and  thermal  stimulation,  but 
the  extent  of  this  and  the  mechaiiistri  has  been  but  little  investi- 
gated. 

The  amount  of  succiis  entericus  secreted  by  the  small  intestine 
has  been  estimated  by  Pn'gl  at  3()()()  c.c.  j)er  day.    The  juice  was 


180  PHARMACOLOGY  OF  THE  GLANDS 

collected  from  a  Thiry-Vella  fistula  and  the  total  amount  estimated. 
Succus  entericus  contains  the  following  enzymes : 

1.  Enterokinase,  which  activates  trypsin. 

2.  Erepsin. 

3.  Inverting  or  hydrolytic  enzymes. 

4.  Nuclease,  also  secretin  and  prosecretin. 

The  nervous  control  of  the  secretion  has  not  been  sufficiently 
investigated  and  there  is  practically  no  known  pharmacology  of 
intestinal  secretion.  Most  investigations  of  the  intestine  have  been 
confined  to  movement,  absorption  and  excretion. 

When  absorbed  or  given  h\T)odermically  the  following  drugs  are 
excreted  into  the  intestine,  probably  by  the  intestinal  juice : 

1.  Ca,  phosphates,  sulphates,  heavy  metals,  such  as  Fe,  Cu, 
Zn,  Bi,  Hg.  Mn,  etc.,  morphin  and  other  alkaloids,  resinous 
cathartics,  toxins,  etc. 

Pancreatic  Secretion. — ^Function  of  the  pancreas — the  secretion  of 
digestive  juices,  probably  also  an  internal  secretion. 

Nerves. — ^\^agus  and  sympathetic  splanchnic.  The  gland  may  be 
stimulated — chemically  as  by  hormones,  and  through  the  nerves. 

1.  Stimulation  by  Parasympathetics. — ^The  pilocarpin  group  of 
drugs,  stimulate  these  nerves. 

2.  Inhibition  through  the  Parasympathetics. — The  atropin  group, 
in  small  doses;  large  doses,  in  some  way  not  understood,  cause 
increased  flow  of  juice. 

3.  Stimulated  reflexly  by  mustard,  spices,  etc.,  acting  on  the 
duodenum. 

4.  Stimulated  chemically  through  the  blood  by  secretin,  a  sub- 
stance found  in  the  duodenum  and  which  may  be  prepared  by  grinds 
ing  the  duodenal  mucous  membrane  with  dilute  hydrochloric  acid. 

The  two  secretions — the  chemical  and  the  nervous,  are  different. 

The  chemical  secretion  (due  to  secretin)  is  clear,  watery,  rich 
in  alkali  and  poor  in  protein  or  organic  matter,  and. contains. but 
little  ferment.  It  occurs  after  the  administration  of  atropin.  The 
nervous  secretion  is  thick,  opalescent,  rich  in  ferments  and  poor  in 
alkali.  The  normal  relation  of  the  two  secretions  is  not  well 
understood. 

Regarding  the  internal  secretion  of  the  pancreas,  there  is  no  phar- 
macology.   No  drugs  are  known  which  influence  it. 


chapter  xvii. 
phar:macology  of  the  kidneys. 

The  pharmacology  of  the  kidney"is  so  important  that  the  student 
is  referred  to  the  monograph  on  the  "Secretion  of  the  Urine," 
by  Cushny/  for  established  facts,  and  Fischer's  "Edema  and 
Nephritis"-  for  suggestions. 

1.  Nerves. — So  far  as  we  know  there  are  no  secretory  nerves  to 
the  kidney.  This  leaves  the  pharmacology  a  matter  of  circulation 
and  direct  action  on  the  secreting  cell.  In  all  cases  the  act  of  secre- 
tion tends  to  dilate  the  vessels,  and  unless  a  drug  which  stimulates 
the  secretory  epithelium  also  constricts  the  vessels,  it  will  act  as  a 
diuretic. 

2.  Blood-pressure. — Unless  there  is  a  blood-pressure  of  40  mm. 
of  Hg  or  more,  practically  no  urine  is  secreted.  After  an  essential 
pressure  is  established,  the  volume  of  urine  secreted  depends  on  the 
^■olume  of  blood  going  through  the  kidneys. 

Theories  of  Diuresis. — Drugs  can  act  only  to  modify  the  normal 
function  of  the  kidney.  This  function  is  the  secretion  and  excretion 
of  urine.  The  mechanism  of  secretion  is  not  satisfactorily  under- 
stood.   The  student  is  advised  to  review  the  theories  of  secretion. 

1.  The  Ludwig — filtration  or  physical  theory. 

2.  Bowman — Heidenhain  or  secretory  theory. 

3.  The  modern  view  of  theory  which  is  more  or  less  a  combination 
of  the  first  two,  with  modifications. 

Important  Factors  Modifying  the  Secretion  of  Urine  .^1.  The  blood- 
pressure:  To  secrete  at  all  the  general  blood-pressure  must  be 
4(J  mm.  of  mercury  or  over. 

2.  Free  water  must  exist  in  the  blood.  Most  of  the  water  in 
the  blood  is  in  a  colloidal  or  combined  form.  Some  is  being  continu- 
ously absorbed  and  some  excreted.  The  volume  probably  depends 
on  the  metabolic  rate.  Acids  or  acidosis  increase  the  capacity  of 
the  proteins  to  hold  water  and  lessens  diuresis.  Alkalies,  salts,  etc., 
lessen  the  water-holding  capacity  of  the  tissues  and  so  increase 
diuresis.     Man^-  experimental  facts  support  this  theory. 

3.  Ab.sorption  from  the  tubules  seems  an  important  factor  in 
governing  the  amount  of  urine  excreted.    It  may  be  assumed  that 

•  Longmans,  Green  &  Co.,  1917. 
'  Wiley  &  Sons. 


182  PHARMACOLOGY  OF  THE  KIDNEYS 

on  passage  through  the  tubules  some  of  the  secretion  water  may  be 
reabsorbed,  just  as  it  would  be  on  passage  through  the  intestine: 
Diuretic  salts  then,  may  act  by  preventing  reabsorption  from  the 
tubules  just  as  cathartics  act  by  preventing  absorption  from  the 
intestines.  In  both  cases  there  may  also  be  a  direct  stimulating 
action  on  the  parenchj^matous  tissues. 

4.  Vasodilation. — Almost  all  substances  on  passage  through  the 
kidneys  cause  a  vasodilation.  If  such  substances  do  not  injure  the 
parenchymatous  tissues  they  act  as  diuretics.  Some  substances 
which  have  a  decided  diuretic  effect  in  minute  amounts,  are  very 
harmful  in  slightly  greater  concentrations.  Cantharidin  and  mer- 
cury are  examples. 

Nerves  of  the  Kidney. — The  kidney  is  innervated  by  the  vagus 
and  by  the  splanchnics,  through  the  celiac  ganglion.  These 
nerves,  however,  are  not  secretory  but  govern  the  vessels.  The 
splanchnic  is  the  chief  motor  nerve  of  the  kidney  and  each  is  dis- 
tributed to  the  kidney  of  the  same  side. 

Diuretics.^ — Since  there  are  no  secretory  nerves  to  the  kidney, 
diiu-etics  must  act,  either:  1.  By  increasing  the  volume  of  blood 
through  the  kidney. 

2.  By  direct  stimulation  of  the  secreting  cells. 

3.  By  lessened  absorption  from  the  tubules. 

4.  By  liberation  of  colloidal  water  from  the  tissue  cells. 

5.  By  a  combination  of  all  or  any  of  these  possibilities. 

Give  the  evidence  for  and  against  each  of  these  possible 
mechanisms. 

The  chief  diuretics  are: 
,     1.  Caffein  compounds. 

2.  The  digitalis  groups — in  some  conditions — edema. 

3.  Pituitary  extract — not  used  for  this  purpose. 

4.  Salines — especially  alkaline  and  absorbable  salts. 

5.  Alkaline  iodides. 

6.  Mercurials — especially  when  there  is  little  catharsis. 
Antidiuretics. — All  substances  that  increase  sweating  without  the 

introduction  of  fluid: 

1.  Pilocarpin. 

2.  Arecolin. 

3.  Antipyretics. 

4.  Heat. 

5.  Camphor. 

6.  Large  doses  of  opium. 

7.  Ammonium  acetate  and  citrate. 


TLATE  VII 


CAFFEINE 

An  alkaloid  existing  iu  cofiFee, 
tea,  guarana,  and  cola  nut. 


Classified  as  : 

Cerebral  stimulant. 
Cardiac  stimulant. 
Respiratory  stimukint. 
Diuretic. 

Physiologic  action  : 

Kervous  System. 

Cerebrum.  Stimulates 
cortex,  increasing  the  ac- 
tivity of  psychic  func- 
tions. 

Medulla.  Stimulates  res- 
piratory center  and  vaso- 
motor center.  Vagus  cen- 
ter may  be  stimulated, 
but  the  eflect  masked  by 
the  direct  effect  upon  the 
lieart. 

Muscular  System.      Initability 
tissue  increased. 


Vagus  Center 

Vaso  Motor 

Center 
Cervical 
Sympathetic 


Voluntary 
Muscle 


and 


—Solar  Plexus 


Circulation.     Arterial  pressure  increased  by  vasomotor  activity. 

Heart.  Stiinulate>  heart  muscle,  producing  acceleration  of 
the  pulse. 

Capillary  area.  Contracts  arterioles  by  stimulation  of  va.so- 
niDtor  centev  in  the  me<lulla,  and  probably  also  by  direct 
action  upon  the  constrictor  fibers  in  the  vessel  walls. 

I'^/rrftiiiii. 

Kidneys.  Stimulates  excretory  function,  botli  of  the  glom- 
eruli and  the  renal  einthelium,  causing  increase  of  water 
and  of  solids,  the  increase  of  water  being  more  marked. 
The  rliuretic  effect  may  be  prevented  by  the  vasomotor 
action. 


The  red  color  indicates  stimulation 

t)V  ('all'cine. 


CAFF BIN 


183 


Elimination  of  Drugs  by  the  Kidneys. — Practically  all  drugs  that 
are  absorbed  may  be  eliminated  more  or  less  by  the  kidney.  They 
may,  however,  be  partially  oxidized  or  conjugated  before  elimina- 
tion. Some  drugs  that  injure  the  kidney  to  any  great  extent  may 
prevent  the  flow  of  urine  and  therefore  may  be  but  slightly 
eliminated  by  that  channel. 

Make  a  record  of  the  excretion  of  each  drug  studied. 

Theories  of  Urinary  Secretioti  as  Outlined  by  Cuslmy  in  Secretion 
of  Urine. — At  present  there  are  three  theories  of  urinary  secretion: 

1.  The  Bowman — Heidenhain  theory. 

2.  The  Ludwig  theory. 

3.  The  modern  theory,  which  is  more  or  less  of  a  combination  of 
the  other  two  theories,  and  has  been  built  up  by  studying  the  others. 
It  takes  part  of  both  and  rejects  parts  of  both,  and  is  not  yet  satis- 
factory in  all  details.  The  following  is  a  summary  of  the  essential 
points  and  differences  of  each  theory. 


Functions  of  capsule 
The  filtrate  is  . 


Volume   of   filtrate 


Tubular  epithelium,  j 
functions  of 


Bowman. 
Heidenhain. 

/  Secretion  by  vital 
acti\dty 

Deproteinized 
plasma 

Approximately 
same  as  urine 

Primarily  secre- 
tory; some  ab- 
sorption under 
exceptional  con- 
ditions 


Ludwig. 

Filtration  purely 
physical 

Deproteinized 
plasma 

Somewhat  larger 
than  urine 

Considerable  infu- 
sion to  blood 
under  excep- 
tional conditions 


Modern 
theory. 

Filtration     purely 

physical. 
Deproteinized 

plasma. 
Very  much  larger. 

Purely  absorption, 
but  a  selective 
absorption. 


The  modern  view  accepts  the  filtration  and  absorption  of  Ludwig, 
but  supplements  them  when  necessary  by  the  vital  activity  postu- 
lated by  Heidenhain.  Accorfling  to  the  modern  theory  the  secretion 
of  urine  consists  of  two  distinct  processes:  (1)  A  purely  physical 
process  which  consists  of  a  filtration  through  the  glomerulus.  (2) 
Selective  reaborption  through  the  tubules;  this  selective  absorption 
depends  on  the  vital  activity  of  the  epithelium. 


CAFFEIN. 

Caffein  is  used  mainly  as  (1)  a  diuretic,  and  (2)  as  a  stimulant 
to  respiration  and  circulation;  (3)  for  its  influence  on  muscle,  and 
(4)  for  its  action  on  the  nervous  system.  Experiments  will  illustrate 
this  action. 

1.  The  Diuretic  Action  of  Caffein. — Caft'ein  compounds  are  the 
diuretic*  drugs  jjar  excellence.     Many  laboratory  exercises  on  this 


184  PHARMACOLOGY  OF  THE  KIDNEYS 

point  fail  because  they  do  not  consider  the  fundamentals  of  urine 
secretion  or  the  condition  in  which  cafTein  acts  best  as  a  diuretic. 
First,  the  kidneys  cannot  secrete  water  unless  water  is  present. 
While  the  blood  normally  contains  over  90  per  cent,  water,  this  water 
is  apparently  in  combination  with  colloid  material  and  only  free 
water  can  be"  secreted.  In  those  clinical  cases  where  caffein  com- 
pounds act  to  the  best  advantage,  the  tissues  are  water  logged 
either  because  of  inadequacy  on  the  part  of  the  heart  or  changes 
in  the  proteins  or  salt  retention.  CafTein  under  these  conditions 
causes  a  diuresis  either  by  causing  a  greater  elimination  of  the  free 
water  or  by  liberating  some  of  the  combined  water.  In  normal 
animals  the  change  caused  by  caffein  on  diuresis  is  so  small  that,  as 
a  class  experiment,  it  is  unsatisfactory.  Only  as  much  water  as  is 
taken  in  can  be  poured  out,  and  in  normal  conditions  this  pouring 
out  or  urination  proceeds  at  a  constant  rate  and  is  hastened  but  little 
by  diuretics.  To  make  a  laboratory  expcx'iment  show  the  real  action 
of  caffein  on  the  kidneys,  the  animal  should  be  given  a  large  volume 
of  liquid  a  short  time  before  the  caffein  is  administered. 

Mechanism  of  the  Action  of  Caffein  Compounds  on  the  Kidney: — 
The  action  of  caffein  is  direct  on  the  kidney  because : 

1.  There  are  no  secreting  nerves  to  the  kidney;  it  occurs  after 
section  of  all  nerves  and  on  the  isolated  kidney,  and  after  degenera- 
tion of  the  nerves. 

2.  The  fluids  in  the  other  tissues  are  not  changedu 

3.  The  kidney  increases  in  volume,  when  secreting,  (a)  The 
action  therefore  is  local,  but  may  be  either  on  the  vessels — a  cir- 
culatory action  or 

(6)  It  may  be  an  action  on  the  secreting  cell.  Opinion  at  present 
favors  a  direct  action  on  the  secreting  cell: 

1.  Because  Rost^  has  found  that  the  flow  of  urine  is  increased — 
only  when  considerable  caffein  passes  into  the  urine. 

2.  Richards  and  Plant^  have  shown  that  diuresis  occurs  with 
caffein  even  when  there  is  no  change  in  kidney  volume. 

Experiment  I. — Action  of  Caffein  on  the  Heart,  Respiration  and 
Kidneys. — 1.  Prepare  a  dog  for  blood-pressure  and  respiratory 
tracing  and  for  injection  into  the  femoral  vein.  Insert  urethral 
cannulse  and  by  means  of  a  Y-tube  unite  these  so  that  the  excretion 
from  both  kidneys  flows  from  a  single  tube.  Record  the  secretion 
in  drops  by  means  of  a  signal  magnet;  also  measure  it. 


1  Arch.  f.  Anat.  u.  Physiol.,  1901,  p.  534. 

2  Jour,  of  Pharm.,  1915,  vii,  485. 


CAFFEIN  185 

2.  Make  a  tracing  showing  the  normal  blood-pressure,  respira- 
tion and  urine  secretion  for  fifteen  to  thirty  minutes. 

3.  Inject  into  the  femoral  vein  5  per  cent,  of  the  weight  of  the 
animal  of  0.9  per  cent.  XaCl. 

4.  Measure  the  urine  secretion  as  before  for  fifteen  to  thirty 
minutes. 

5.  Inject  slowly  into  the  vein  10  mg.  per  kilo  weight  of  cafi'ein, 
diuretin  or  augurin.  Note  the  influence  on  blood-pressure,  respira- 
tion and  urinary  flow  for  thirty  minutes.  Compare  results  with 
2,  3  and  4. 

6.  After  the  action  of  caffein  has  been  studied  inject  10  c.c.  per  kilo 
of  warm  8  per  cent,  sodium  sulphate  every  five  minutes  or  until  the 
secretion  of  the  urine  is  increased  markedly.  While  the  flow  of  urine 
is  rapid,  inject  10  c.c.  per  kilogram  of  body  weight  6  per  cent, 
mucilage  of  acacia  and  note  the  effect.  This  has  been  recommended 
by  Bayliss  in  cases  of  hemorrhage,  since  it  sustains  blood-pressure 
better  than  physiological  saline.  It  does  this  because  it  holds  water 
in  the  bloodvessels. 

Experiment  II. — Diuretics  frequently  while  raising  the  pressure  or 
stimulating  the  kidney  constrict  the  kidney  vessels  and  to  this 
extent  work  against  the  flow  of  urine,  since  this  flow  depends  on 
the  volume  of  blood  circulating  through  the  kidney.  To  avoid  this 
chloral  is  sometimes  prescribed  with  the  diuretic  as  a  "corrective. 
It  is  given  with  digitalis  for  the  same  reason. 

Prepare  a  dog  as  in  Experiment  I:  (a)  Take  tracings  of  normal 
blood-pressure,  respiration  and  urine  flow  and  injection  into  femoral 
vein.  Inject  1  c.c.  of  1  per  cent,  caffein  per  kilo  body  weight.  Repeat 
the  dose  every  ten  minutes  for  three  times  and  get  records  of  the 
effect  for  thirty  minutes.  Then  (b)  inject  intravenously  0.3  gram 
per  kilo  of  chloral  hydrate  (3  c.c.  10  per  cent.).  Take  three  to  five 
minutes  for  this  injection.  Compare  the  rate  of  secretion  before 
and  after  the  administration  of  chloral,  (c)  Acetates  are  sometimes 
prescribed  to  aid  in  diuresis.  The  superiority  of  theobromin  sodium 
acetate  as  a  diuretic  is  somewhat  due  to  the  acetate.  Inject  1  gram 
per  kilo  of  sodium  acetate  (10  c.c.  10  per  cent,  per  kilo)  and  note 
results  for  thirty  minutes.  Potassium  acetate  is  frequently  pre- 
scribed with  infusion  of  digitalis;  why  not  use  it  here?  Has  it  any 
advantages  over  .sodium  acetate? 

Experiment  HI. — Action  of  Caffein  on  the  Frog. — Inject  2  c.c. 
of  0.r>  i;cr  cent,  cafl'ein  in  water  into  the  anterior  lymph  sac  and  make 
observations  every  few  minutes.    Notice  the  changes  in  irritability 


186 


PHARMACOLOGY  OF  THE  KIDNEYS 


■ — muscle  cramps  and  a  final  paralysis.  (Note  the  solubility  of  this 
alkaloid  in  water.) 

Compare  the  actions  of  caffein,  strychnin  and  picrotoxin. 

Experiment  IV. — Action  of  Caffein  on  the  Frog's  Heart. — Pith  a 
frog  and  take  heart  tracings  by  the  suspension  method.  Isolate 
and  stimulate  the  vagus.  Drop  1  per  cent,  of  caffein  solution  slowly 
on  the  heart;  take  tracings  and  note  whether  or  not  there  is  any 
change  in  the  vagus  action.  Continue  the  tracing  until  definite 
action  is  obtained. 


Fig.  40. — Method  of  arranging  muscle  for  recording  fatigue  contractions. 


Experiment  V. — Action  of  Caffein  on  the  Turtle  Heart. — Pith  a  turtle, 
expose  vagi  and  take  a  record  of  the  heart  by  the  suspension  method. 
Test  irritability  of  both  vagi.  Irrigate  the  heart  with  0.5  per  cent, 
caffein  by  dropping  the  solution  directly  on  the  heart.  Determine 
whether  or  not  there  is  any  change  in  the  irritability  of  the  vagi. 

Experiment  VI. —  The  Action  of  Caffein  on  Turtle  Heart  Strips. — 
Prepare  and  take  tracings  of  a  ventricle  strip  suspended  in  0.8  per 
cent,  saline.  When  a  good  record  is  being  obtained  add  sufficient 
2  per  cent,  caffein  in  the  same  solution  so  that  the  concentration  of 
the  liquid  in  which  the  strip  beats  is  0.1  per  cent,  caffein.  After 
thirty  minutes  change  the  concentration  to  0.5  per  cent,  caffein; 
continue  this  until  definite  action  is  obtained. 

Experiment  VII. — Action  of  Caffein  on  the  Reflex  Time  of  Frogs. — ■ 
Pith  the  animal  and  prepare  for  reflex  time  as  under  alcohol  either 
by  Tiirck's  method  or  by  electrical  stimulation.  Determine  the 
average  time  of  five  reflexes.    Then  inject  1  c.c.  of  0.5  per  cent. 


SALINE  DIURETICS  187 

caffein  in  water  into  the  anterior  lymph  sac  and  after  fifteen  minutes 
again  determine  the  reflex  time.  Take  average  of  at  least  five 
determinations. 

Experiment  VIII. — Action  of  Caffein  on  Respiration. — Anesthetize 
a  small  dog  with  ether  and  prepare  to  measure  blood-pressure,  and 
respiratory  volume  with  a  spirometer.  Place  a  cannula  in  the 
femoral  vein  for  injection.  Take  a  normal  tracing  and  measure  the 
expired  air  in  minute  intervals.  Measure  volume  per  minute  and 
respiratory  rate.  Also  make  record  of  the  respiration  on  the  drum 
from  the  chest  movements.  This  can  be  done  by  a  rubber  tube 
around  the  chest  to  which  a  tambour  is  attached. 

When  normal  tracings  and  volume  measurements  ar^  obtained, 
inject  1  c.c.  of  3  per  cent,  morphin  slowly  into  the  femoral  vein  and 
note  the  changes  in  respiration  every  five  minutes  for  fifteen  minutes. 
Then  inject  intravenously  0.5  c.c.  per  kilo  of  1  per  cent,  solution 
of  caffein  and  again  measure  as  before.  Repeat  injections  if 
necessar}'.      Tabulate  results. 

Experiment  DC. — Repeat  Experiment  IX  under  cocain,  page  148, 
but  use  1  c.c.  0.5  per  cent,  caffein. 


SALINE  DIURETICS. 

All  salts  which  are  eliminated  by  the  kidney  are  diuretics.  In 
class  experiments,  sodium  sulphate  is  often  used  and  given  intra- 
venously. However,  when  sulphates  are  given  by  mouth  they  are 
so  slightly  absorbed  that  little  diuresis  results.  This  is  especially 
true  if  they  produce  catharsis.  One  must  distinguish  carefully 
between  the  theoretical  and  practical  value  of  such  procedures. 
Only  salts  that  are  absorbed  and  are  excreted  by  the  kidneys  are 
practical  diuretics.  KNO3  is  diuretic  when  given  by  mouth;  if  it 
is  given  intravenously,  the  potassium  is  so  depressant  that  the 
action  of  the  potassium  may  be  so  great  that  it  will  injure  the  heart. 
Potassium  or  sodium  acetates  are  the  most  used.  They  have  a 
double  action,  first  the  salt  action,  and  second  the  alkaline  reaction. 
They  are  oxidized  to  carbonates  in  the  body. 

Salts  may  act  as  diuretics  in  three  ways: 

1.  By  direct  action  on  the  kidney. 

2.  By  lessening  the  water-holding  capacity  of  the  body  colloids. 

3.  By  increasing  the  alkalinity,  as  in  the  case  of  the  acetates.- 
Acidosis  decreases  the  urinary  flow  by  increasing  the  water-holding 
capacity  of  the  body  colloids. 


188  PHARMACOLOGY  OF  THE  KIDNEYS 

Experiment  I. — Prepare  a  dog  for  measurement  of  blood-pressure, 
respiration  and  urine  flow.  Inject  intravenously  5  per  cent,  of  the 
animal's  weight  of  0.85  per  cent,  of  NaCl  solution. 

1.  Measure  urine  flow  for  thirty  minutes. 

2.  Inject  slowly  20  c.c.  of  ^  acid  (HCl).  Watch  carefully  that 
the  injection  does  not  kill  the  animal.  Measure  the  urine  for  thirty 
minutes. 

3.  Inject  40  c.c.  j-q  of  Na2C03  slowly  and  measure  the  urine  for 
thirty  minutes. 

4.  Inject  slowly  3  per  cent,  of  KNO3  until  the  heart  shows  symp- 
toms of  depression.    Measure  the  urine  for  thirty  minutes. 

5.  Inject  30  c.c.  of  10  per  cent.  Na2S04  and  measure  the  urine 
for  thirty  minutes. 

6.  Inject  10  c.c.  of  y^  HCl  and  note  the  influence  on  the  flow  of 
urine. 

7.  Inject  10  c.c.  of  y^  Na2C03  and  note  the  effect  for  thirty 
minutes. 

Experiment  II. — Diuretic  Action  of  Caffein  on  the  Normal  Animal. 
— 1.  Select  a  male  rabbit.    Catheterize  until  the  bladder  is  empty. 

2.  At  the  end  of  an  hour  catheterize  again  and  measure  the  amount 
of  urine. 

3.  Inject  subcutaneously  10  mg.  per  kilo  of  body  weight  of 
citrate  cafi^ein  in  water. 

4.  At  the  end  of  an  hour  catheterize  again  and  measure  the 
volume  of  urine. 

5.  Compare  and  discuss  the  results.  What  do  you  conclude  as  to 
the  diuretic  action  of  caffein. 

Experiment  III, — 1.  A  group  of  from  ten  to  twenty  students 
should  work  together.  Each  one  should  empty  the  bladder  com- 
pletely at  the  beginning  of  the  experiment. 

2.  Then  each  one  should  drink  300  c.c.  of  water. 

3.  At  the  end  of  an  hour  empty  the  bladder  and  measure  the 
volume  of  the  urine. 

4.  Then  each  person  should  drink  300  c.c.  of  water,  one-third  of 
the  students  taking  2.5  grains  of  caffein,  one-third  5  grains  and  one- 
third  10  grains.^ 

5.  At  the  end  of  one  hour  empty  the  bladder  and  measure  the 
volume  of  urine. 

6.  Compare  results  and  discuss  briefly  the  diuretic  action  of  the 
caffein. 

7.  A  second  group  should  carry  through  this  same  experiment 
but  without  drinking  any  water. 


PHENOLSULPHONEPHTHALEIN  189 


PHENOLSULPHONEPHTHALEIN. 

Kidney  Function. — This  drug  is  not  used  in  therapeutics,  but  as 
a  diagnostic  test  of  kidney  function.  When  the  kidneys  are  normal, 
about  60  to  80  per  cent,  of  this  is  excreted  within  two  hours  after 
the  h>i^odermic  injection. 

Experiment  I. — Take  seven  rabbits  and  place  each  in  a  separate 
clean  metabolism  cage.    Two  days  before  the  experiment  inject — 

1.  With  2  c.c.  per  kilo  of  1  per  cent,  arsenious  acid,  AS2O3,  subcu- 
taneously. 

2.  With  1  c.c.  per  kilo  of  10  per  cent,  potassium  bichromate. 

3.  Each  day  for  three  days  preceding  the  experiment,  1  c.c.  per 
kilo  of  0.5  per  cent,  uranium  nitrate. 

4.  Mercuric  chloride,  5  c.c.  per  kilo  of  0.2  per  cent,  for  two  days 
preceding  the  experiment. 

5.  Five  c.c.  per  kilo  of  5  per  cent,  ammonium  oxalate. 
6  and  7.  Controls. 

Empty  the  bladder  of  each  and  inject  hypodermically  2  c.c.  of 
a  6  mg.  per  cubic  centimeter  solution  of  phenolsulphonephthalein. 
Also  give  each  one  20  c.c.  of  0.9  per  cent.  NaCl.  In  two  hours  empty 
the  bladder  of  each  one  and  determine  how  much  of  the  phenol- 
sulphonephthalein has  been  excreted.  Compare  with  the  controls. 
What  is  the  condition  of  the  animals  at  this  time? 

Experiment  II. — Anesthetize  each  of  the  animals  with  ether. 
Insert  a  bladder  cannula  for  collection  of  urine  and  a  cannula  in  the 
jugular  vein  for  injection  of  solutions.  Wait  ten  minutes  between 
each  injection  and  measure  the  urine  for  each  period. 

1.  Inject  20  c.c.  of  0.19  per  cent.  NaCl. 

2.  Inject  5  c.c.  of  2  per  cent,  sodium  citrate. 

;3.  Inject  2  c.c.  of  0.05  per  cent,  citrated  caffein. 

4.  Inject  10  c.c.  of  0.5  per  cent,  theobromine  sodium  salicylate. 

5.  Inject  2  c.c.  of  0.5  per  cent,  calomel  in  1  per  cent,  sodium 
thiosulphate. 

Make  a  chart  showing  the  efl'ect  of  each  drug  on  each  animal  and 
compare  with  the  normal  animals. 

Experiment  m. — Inject  subcutaneously  with  aseptic  precautions 
2  c.c.  of  a  0.5  mg.  solution  containing  per  cubic  centimeter  of 
phenolsulphonephthalein  into  10  students.  In  one  or  two  hours 
determine  the  amount  excreted. 

If  a  colorimeter  is  not  available  the  amount  of  coloring  material 
can  be  determined  as  follows:    (a)  Place  the  urine  in  a  500  c.c.  or 


190  PHARMACOLOGY  OF  THE  KIDNEYS 

1000  c.c.  graduate;    add  sufficient  NaOH  to  color.     Make  up  to 
100  c.c.  or  200  c.c.  mark. 

(6)  Place  0.5  mg.  per  cubic  centimeter  of  phenolsulphonephtha- 
lein  or  the  amount  injected  subcutaneously  in  another  graduate  of 
the  same  size.  Alkalinize  with  NaOH  and  dilute  until  the  color 
matches  the  urine.  From  the  degree  of  dilution  of  the  standard 
required  to  match  the  urine  the  percentage  excreted  can  be 
determined. 


CHAPTER  XVIII. 
PHARIVIACOLOGY  OF  SWEAT-GLANDS. 

Function. — The  sweat-glands  are  excretory  organs  for  salts  and 
water  mainly.  There  is  some  nitrogenous  matter  also,  but  not  of 
sufficient  amount  to  reckon  in  metabolic  experiments.  In  cases  of 
uremic  poisoning  and  other  pathologic  states  the  nitrogen  elimina- 
tion by  the  sweat-glands  may  be  increased. 

Distribution  of  the  Glands. — 1.  In  man  and  horses  the  whole 
surface  of  the  skin  contains  sweat-glands. 

2.  In  dogs  and  cats  sweat-glands  are  found  on  the  feet  only. 

3.  Rabbits,  rats  and  mice  have  no  sweat-glands. 
Innervation. — The  sweat-glands  are  under  the  direct  control  of 

sjVTnpathetic  nerves  and  the  drugs  acting  on  the  secretion  of  sweat 
act  mainly  on  the  nerve-endings,  although  there  are  centrally  acting 
diaphoretics. 

We  do  not  know  that  any  drugs  act  directly  on  the  glands.  The 
striking  peculiarity  of  the  nerves  to  the  sweat-glands  is  that  although 
sympathetic  they  are  stimulated  by  pilocarpin  and  paralyzed  by 
atropin  in  a  manner  similar  to  autonomic  nerves;  likewise  epinephrin 
is  without  influence  on  them.  They  provide  the  one  great  exception 
to  the  rule  that  epinephrin  stimulates  sympathetic  nerve-endings 
and  pilocarpin  stimulates  autonomic  endings. 

Drugs  that  act  on  the  nerves  governing  the  secretion  of  sweat 
may  act  (1)  centrally  and  (2)  peripherally. 

The  drugs  acting  on  the  sweat  centers  are  ammonium  salts, 
picrotoxin,  camphor  and  strychnin  to  some  extent. 

The  proof  that  they  act  centrally  is  that  they  fail  to  act  after 
section  of  the  nerve  to  the  part  or  after  high  section  of  the  cord. 
The  location  of  the  sweat  center  is  not  definitely  known.  It  is, 
however,  above  the  fifth  spinal  segment,  because  cases  in  the  human 
are  known  in  which  fractures  at  this  level,  with  injury  to  the  cord, 
stopped  sweating  below  the  injury,  not  above.  The  center  is  prob- 
ably located  in  the  medulla.  In  the  cat,  in  addition,  it  has  been 
established  that  there  are  at  least  two  spinal  sweat  centers,  one  for 
the  forelimbs  in  the  lower  cervical  and  another  for  the  hindlimbs 
in  the  dorsal  region.  Diaphcjretics  acting  on  the  nerve  endings  are 
pilocarpin,  muscarin,  eserin,  and  arecolin. 


192  PHARMACOLOGY  OF  SWEAT-GLANDS 

Proof  that  the  action  is  peripheral,  is  that  they  act  after  section 
of  the  nerves.  Other  drugs  and  agents  acting  centrally.  Most 
drugs  that  exert  an  antipyretic  effect  act  centrally  and  in  large 
doses  cause  sweating. 

The  sudorific  glands  are  affected  in  the  same  way  as  the  sweat- 
glands,  but  have  not  been  so  carefully  studied. 

ENDOCRINAL  PHARMACOLOGY. 

Concerning  the  pharmacology  of  the  endocrinal  glands,  we  must 
say  that  more  numerous  experiments  have  been  made  in  feeding 
glands  and  extracts  and  some  definite  results  on  blood-pressure, 
respiration,  etc.,  have  been  gotten,  but  regarding  the  modification 
of  the  function  of  each  of  these  glands  by  drugs  or  otherwise,  little 
has  been  learned.  Those  glands  like  the  adrenals  that  have  a 
nervous  mechanism,  can  be  stimulated  by  drugs  like  nicotin  and 
perhaps  depressed  by  general  depressants,  but  little  of  anything 
definite  has  yet  been  learned. 


CHAPTER  XIX. 

PH.\RMACOLOGY  OF  THE  LIVER,  MAMMARY  GLANDS, 
UTERUS  AND  BLADDER. 

PHARMACOLOGY  OF  THE  LIVER. 

Main  Functions  of  the  Liver. 

1.  Secretion  of  bile. 

2.  Carbohydrate  transformations. 

3.  Sympathetic  functions. 

4.  Interrelative  functions  with  other  organs. 

Secretion  of  Bile. — This  is  controlled  by  the  vagus  and  splanchnic 
nerves. 

Drugs  Influencing  the  Formation  of  Bile  are  Termed  Clwla- 
gogues. — The  bile  stimulants  are: 

1.  Bile  itself. 

2.  Bile  salts. 

3.  Soaps. 

4.  Albuminoses. 

5.  Dilute  HCl. 

6.  Salicylates  and  benzoates. 

7.  Calomel. 

Drugs  Stimulating  movement  of  the  Gall-bladder. — Pilocarpin. 

Drugs  Lessening  Movement  of  Gall-bladder. — Atropin.  Atropin 
is  frequently  used  in  gall-stone  colic  because  of  this  property. 

Excretion  of  Drugs  by  the  Bile. — Cu,  Pb,  Hg,  menthol,  methylene 
blue,  am}'l  alcohol,  hexamethylenamin  and  other  drugs  have  been 
reported  in  the  bile.  They  occur,  however,  only  in  traces,  except 
hexamethylenamin,  which  is  said  to  be  excreted  in  quantities 
sufficient  to  sterilize  the  bile. 

The  Glycogenic  Function  of  the  Liver. — This  is  influenced  by  a  large 
number  (;f  drugs,  but  tlie  action  may  be  indirect.  In  fact,  while 
it  is  well  known  that  the  liver  is  exceedingly  important  in  carbo- 
hydrate metabolism,  the  mechanism  of  the  action  is  little  under- 
stood, and  while  the  action  of  many  drugs  on  this  metabolism  has 
been  studied  to  some  extent,  it  is  the  liarmful  action  that  has  been 
most  studied.  \'ery  little  is  known  of  drugs  that  have  a  beneficial 
13 


194  PHARMACOLOGY  OF  THE  MAMMARY  GLANDS 

effect  on  the  glycogenic  function  of  the  liver.    The  harmful  effect 
is  usually  manifested  by  an  increase  in  the  sugar  content  of  the  blood 
and  by  glycosuria,  though  a  hypoglycemia  may  also  occur. 
Drugs   Influencing   the   Carbohydrate   Metabolism  of  the  Liver. — 

1.  Epinephrin  is  necessary  for  the  normal  process;  in  large 
amounts  hypodermically  it  causes  glycosuria. 

2.  Salts  injected  intravenously  cause  hyperglycemia  and  glyco- 
suria. 

3.  It  may  be  influenced  in  the  same  way  by  many  drugs  acting 
on  the  nervous  system,  as  strychnin,  caffein  and  others. 

4.  Certain  other  drugs  which  greatly  depress  the  animal,  like 
hydrazins,  peptons,  etc.,  given  intravenously,  may  cause  hypo- 
glycemia. 

The  other  chemical  functions  of  the  liver,  liKe  the  formation  of 
urea,  its  action  in  fat  metabolism,  its  function  in  blood  coagulation, 
etc.,  are  markedly  influenced  by  the  internal  secretions  of  other 
glands  like  the  thyroid,  adrenals,  etc.,  and  also  by  chemical  agents. 
The  actions  of  phosphorus,  hydrazin,  arsenic,  etc.,  on  the  liver  are 
striking. 

PHARMACOLOGY  OF  THE  MAMMARY  GLANDS. 

The  fimction  of  these  is  milk  secretion.  They  are  markedly 
influenced  by  the  internal  secretion  of  the  ovaries,  and  probably 
they  give  off  an  internal  secretion,  but  distinct  evidence  of  this 
has  not  been  presented.  Drugs  theoretically  might  stimulate  or 
decrease  the  volume  of  milk  secreted.  As  a  matter  of  fact,  however, 
drugs  have  little  influence  on  milk  secretion. 

Nerves.^ — Experimental  investigation  shows  that  the  mammary 
gland  is  little,  if  at  all,  under  the  direct  influence  of  the  nervous 
system.  That  such  nerves  exist,  however,  is  unquestionable,  as 
shown  by  the  marked  influence  of  emotional  states  on  milk  secretion. 

Mackenzie,^  from  an  investigation  of  the  mechanism  of  milk 
secretion,  concludes  that: 

1.  The  secretory  activity  of  the  gland  is  not  under  the  influence 
of  the  nervous  system. 

2.  Agents  that  modify  the  secretion  reach  the  gland  by  the  blood. 

3.  Extracts  of  the  pituitary,  corpus  luteum,  pineal  body,  the 
uterus  and  the  mammary  gland  itself  stimulate  secretion. 

4.  The  pituitary  gland  is  the  most  active  stimulant. 

5.  Inhibitory  hormones  are  produced  by  the  fetus  and  placenta. 

1  Quart.  Jour,  of  Exp.  Physiol.,  1911,  iv,  305. 


PHARMACOLOGY  OF  THE   UTERUS  195 

6.  Drugs  such  as  pilocarpin  and  atropin  that  influence  the 
secretion  of  most  glands  are  without  effect. 

7.  Because  of  the  ineffectiveness  of  the  drugs  mentioned  in  (6) 
it  is  conchided  there  are  no  demonstrable  secretory  nerves  to  these 
glands.  This  is  supported  by  electrical  stimulation  of  nerves  going 
to  the  glands. 

Lactagog^ues. — Practically  there  are  none.  The  secretion  of  milk 
is  said  to  be  lessened  by  the  administration  of  KI  and  by  the  local 
application  of  belladonna.  In  the  latter  case  the  analgesic  action 
on  the  sensory  nerves,  may  be  confused  with  an  action  on  the 
secretory  mechanism. 

Elimination  of  Drugs  in  the  Milk. — Iodides,  bromides,  salicylates 
antipATin,  arsenic,  mercury,  hexamethylenamin,  morphin,  atropin, 
etc.,  have  been  found  in  the  milk  of  animals. 

PHARMACOLOGY  OF  THE  UTERUS. 

The  uterus,  like  the  intestine,  is  in  more  or  less  continuous 
movement.  These  movements  are  automatic,  that  is  not  initiated 
by  nerve  impulses,  but  controlled  by  the  nerves. 

The  motor  nerves  are  autonomic,  from  the  nervus  pelvicus 
(Erigen's)  and  inhibitory  from  the  sympathetic  from  the  hypo- 
gastric plexus. 

Drugs  modifying  uterine  movements,  may  act: 

1.  On  the  muscle  directly,  (a)  Hypophysis  extracts,  (6)  barium 
salts  and  (c)  ergot. 

Hypophysis  acts  directly  on  the  muscle  and  causes  maximal  con- 
traction.   Barium  also  acts  directly  on  the  muscle  and  stimulates  it. 

2.  On  the  ganglion  cells,  (a)  Nicotin:  The  result  of  nicotin 
varies,  depending  on  the  species  of  animal  and  the  predominating 
ganglion  cells,  much  in  the  same  way  as  epinephrin. 

3.  On  the  nerve-endings. 

Epinephrin. — The  uterus  receives  sympathetic  nerves  from  the 
hypogastric  plexus.  The  action  of  epinephrin  is  identical  with 
stimulation  of  this  plexus,  but  it  differs  in  different  animals.  The 
uterus  receives  through  the  sympathetic  both  motor  and  inhibitory 
fibers.  The  predominating  action  varies  with  the  animal  and  with 
the  condition  of  the  animal.  Thus,  stimulation  of  the  hypogastric 
nerves  of  the  non-pregnant  cat  causes  inhibition.  In  the  pregnant 
state  it  causes  contraction.  In  the  rabbit  the  usual  result  in  all 
cases  is  contraction.  In  the  dog,  contraction  is  followed  by  inhibi- 
tion.   Epinephrin  acts  similarly  to  stimulation  of  this  plexus. 


196  PHARMACOLOGY  OF   THE   UTERUS 

Atropin. — In  small  doses  atropin  may  increase  the  action,  but 
in  larger  amounts  always  inhibition.  This  is  the  usual  atropin 
action  on  autonomic  nerves,  except  the  primary  stimulation  which 
in  most  regions  is  absent.  ' 

Physostigmin  and  PUocarpin.  —  These  drugs  exert  their  usual 
action  on  autonomic  nerve  ends — stimulation. 

Ergot. — The  fluidextract  of  ergot  is  the  principal  preparation 
used  in  medicine.  The  recent  work  of  Dale  has  simplified  greatly 
the  knowledge  of  ergot  action.  It  contains  three  active  ingredients : 
ergotoxin,  tyramin  and  ergamin.     cl 

Ergotoxin  and  tyramin  act  like  epinephrin  and  stimulate  the  myo- 
neural junction  of  the  true  sympathetic  nerves.  There  are  some 
differences,  however,  between  the  action  of  epinephrin  and  these. 
The  action  and  differences  are  as  follows: 

1.  Epinephrin  acts  on  both  motor  and  inhibitory  nerves,  and 
under  special  conditions,  therefore,  may  cause  a  fall  of  blood- 
pressure. 

2.  Ergotoxin  stimulates  the  vasoconstrictors  only.  Large  doses 
may  paralyze  these,  so  that  after  ergotoxin,  epinephrin  may  cause 
a  fall  in  bloodrpressure. 

3.  Tyramin  acts  on  both  motor  and  inhibitory  nerves,  but  only 
to  a  small  extent  on  the  inhibitory. 

4.  Ergamin  does  not  act  on  the  nerve-endings  at  all,  but  on  the 
non-striated  muscle  directly. 

5.  Different  samples  of  ergot  may  differ  in  action,  depending  on 
the  relative  amounts  of  these  bases  present.  Also  in  pregnant 
animals  when  there  is  a  development  of  sympathetic  nerves  the 
action  varies  from  that  in  the  non-pregnant  animal.  Study  these 
actions  in  detail  from  the  text. 

Experiment  I. — Action  on  the  frog;  take  three  frogs;  give  one 
0.5  c.c.  of  fluidextract  ergotse.  Give  the  second  1  c.c.  and  the  third 
2  c.c.    Inject  into  the  abdominal  lymph  sac. 

Experiment  II. — Action  of  Ergot  on  the  Arterioles. — (a)  Place  a  frog 
on  the  boards  and  examine  the  capillary  circulation  of  the  web  of 
the  foot.  Make  a  sketch  of  the  field  and  give  the  animal  0.5  c.c. 
fluidextract  ergotse  and  repeat  observations  at  five-minute  intervals. 

(b)  Repeat  (a),  using  1  c.c.  of  the  fluidextract. 

(c)  Repeat  (1)  and  (2),  using  the  mesentery  instead  of  the  foot 
for  observations. 

Experiment  III. — Action  of  Ergot  on  the  Blood-pressure,  Respira- 
tion, Pupil  and  Vagus  Tone. — Prepare  a  dog  for  blood-pressure  and 
respiratory  tracings.    Insert  a  cannula  in  the  femoral  vein  for  injec- 


PHARMACOLOGY  OF   THE   UTERUS 


197 


tion.  Isolate  a  loop  of  the  intestine  for  observation  of  the  action 
on  the  capillaries.  Make  normal  tracings  and  inject  the  fliiidextract 
of  ergot,  0.5  c.c.  at  a  time,  and  repeat  every  five  minutes  until  the 
animal  dies.  Note  the  action  on  the  heart,  respiration,  pupil  and 
intestines.  A  tracing  of  the  intestinal  movements  may  be  taken 
by  one  of  the  methods  under  epinephrin. 

Experiment  IV. — Action  of  Ergot  on  the  Heart  Stri2)s. — Prepare  a 
heart  strip,  and  when  it  is  beating  regularly  add  fluidextract  of  ergot 
gradually  until  the  bath  contains  10  per  cent,  of  the  fluidextract. 


Fig.  41.- 


-Frog  on  cork  plate  to  show  method  of  preparation  for  studying  the  circula- 
tion in  the  web  of  the  foot. 


Experiment  V. — Action  of  Ergot  on  the  Uterus. — Take  segments 
of  the  uterus  of  a  guinea-pig,  cat  or  rabbit  and  arrange  for  tracing 
as  with  a  heart  strip.  Keep  the  bath  at  40°  C.  When  it  is  contract- 
ing rhythmically,  add,  drop  by  drop,  some  fluidextract  of  ergot. 

In  the  preparation  of  uterine  strips  certain  precautions  are 
necessary  to  get  results. 

1.  An  anesthetic  if  used  in  removing  the  uterus  acts  to  prevent 
the  rhythmical  movements. 

2.  Shock  or  brutal  manipulations  have  the  same  effect.  It  is 
best  to  remove  the  head  of  the  animal  quickly  with  a  pair  of  large 
scissors  or  a  sharp  knife    Then  the  uterus  is  removed  quickly,  using 


198 


PHARMACOLOGY  OF   THE  UTERUS 


a  forceps  and  scissors — do  not  handle — and  place  in  well-aerated 
warm  (40°  C.)  saline,  and  always  handle  with  these  precautions  in 
mind. 

Experiment  VI. — Study  the  effect  of  ergot  on  the  uterus  when 
injected  intravenously  by  Barbour's  method. 


Fig.  42. — Method  of  examination  of  circulation  in  the  web  of  a  frog's  foot, 
apparatus  consists  of  a  cork  plate  with  a  hole  in  it. 


The 


Experiment  VII. — Standardization  of  Ergot. — No  satisfactory 
method  is  available.  Three  more  or  less  satisfactory  methods  are 
used: 

1.  Blood-pressure  method. 

2.  Cock's-comb  method. 

3.  The  uterine  method:  (a)  Isolated  Uterus:  Experiment  V; 
(b)  in  situ:  Experiment  VI. 

The  blood-pressure  method  is  the  easiest  and  perhaps  the  most 
reliable.  0.08  c.c.  of  the  fluidextract  per  kilo  of  body  weight  should 
cause  a  rise  in  blood-pressure  of  30  mm.  Hg.  in  the  dog. 


PHARMACOLOGY  OF  THE  UTERUS  199 

Anesthetize  a  dog  with  ether.  Keep  the  anesthetic  regular  and 
prepare  for  blood-pressure  and  respiratory  tracings.  Prepare  for 
injection  into  the  femoral  vein.    Then  proceed  as  follows: 

1.  Take  normal  tracing  of  about  three  inches  on  the  drum.  Then 
stop  driun. 

2.  Inject  0.04  c.c.  per  kilo  body  weight  of  the  fluidextract  and 
wait  five  minutes. 

3.  Take  a  three-inch  tracing  on  the  drum.  Stop  drum  and  wait 
five  minutes. 

4.  Then  take  another  tracing.  Keep  this  up  until  three  or  four 
tracings  are  taken.    The  blood-pressure  of  each  will  be  different. 

If  the  first  injection  causes  a  fall  in  pressure  of  more  than  35  mm. 
Hg.  or  a  rise  of  more  than  50  mm.  Hg.,  the  dose  should  be  reduced 
one-half.  If  the  fall  is  less  than  25  mm.  or  the  rise  less  than  24  mm. 
the  dose  should  be  doubled. 

5.  The  same  animal  may  be  used  for  three  or  four  injections 
if  one  allows  sixty  minutes  to  elapse  between  injections. 

Experiment  VDI. —  The  Cock's-comb  Method. — ^This  method  is  used 
by  some  manufacturers  to  determine  the  strength  of  an  unknown 
quantity  of  ergot  by  comparing  its  effects  with  the  effects  of  an 
equal  quantity  of  standardized  ergot.  Leghorn  cocks  with  large 
combs  and  wattles  are  advised;  they  are  used  in  preference  to  the 
others  because  the  common  barnyard  fowl  varies  too  greatly  in 
its  reaction.  The  cock  to  be  used  must  not  be  fed  for  twenty-four 
hours  previously. 

Examine  the  color,  temperature  and  general  appearance  of  the 
comb  and  wattles.  Then  with  a  hypodermic  syringe  inject  deep 
into  the  breast  muscles  5  c.c.  of  a  first-class  preparation  of  fluid- 
extract  of  ergot.  The  drug  may  also  be  given  into  the  crop  with  a 
soft-rubber  catheter. 

Place  the  animal  in  ar  quiet  place  and  observe  it  carefully,  from 
time  to  time,  for  at  least  one  or  two  hours.  Do  you  note  any  change 
in  the  appearance  of  the  comb  and  wattles?  If  so,  at  what  time  after 
the  injection  is  the  change  at  its  maximum?  If  you  had  a  stan- 
dardized preparation  and  a  non-standardized  preparation  of  the 
fluidextract  of  ergot,  could  you  compare  the  relative  strengths  of 
these  two  solutions  by  their  relative  actions  in  the  same  sized  doses 
on  roosters  of  approximately  the  same  size,  age  and  sensitivity  to 
the  drug?  Note  the  action  on  the  intestine.  The  method  is  not 
very  satisfactory. 


200  PHARMACOLOGY  OF  THE  BLADDER 

PHARMACOLOGY  OP  THE  BLADDER. 

The  bladder  is  merely  a  reservoir.  The  muscular  coat  is 
strengthened  at  the  cervix  by  a  circular  coat,  which  acts  as  the 
sphincter  vesicae  internus,  while  around  the  urethra  on  the  outside 
of  the  bladder  is  the  sphinctei-  vesicae  externus.  When  the  urine 
accumulates  to  a  certain  extent  the  pressure  reflexly  stimulates 
the  sphincters. 

Nerves. — The  bladder  receives  motor  fibers  from  the  second  to 
the  third  sacral  nerves — autonomic — through  the  N.  Erigentes 
from  the  hypogastric  plexus.  It  also  receives  sympathetic  fibers 
from  the  second  to  the  fifth  lumbar  nerves,  reaching  the  bladder 
through  the  inferior  mesenteric  ganglion.  Local  application  of 
epinephrin  will  usually  cause  a  relaxation.  Atropin  is  given  in  cases 
of  enuresis  to  inhibit  the  urinary  reflex  by  an  action  on  the  auto- 
nomic nerve-ends.  The  small  amounts  that  escape  in  the  urine  in 
therapeutic  doses  could  scarcely  exert  this  influence. 

Antisepsis. — Various  drugs  are  given  in  cystitis,  etc.,  with  the  idea 
of  disinfecting  the  urine.  Among  these  are  (1)  hexamethylenamin, 
which  acts  only  in  acid  reaction;  (2)  sodium  benzoate  and  salicy- 
late, (3)  various  volatile  oils  such  as  copaiba,  cubeb,  oleum  santali. 
A  study  of  these  comes  more  directly  under  antiseptics,  than  under 
the  dynamics  of  the  bladder. 


CHAPTER  XX. 

PHARMACOLOGY  OF  THE  MUSCLES. 

The  muscles  are  divided  into  two  great  groups: 
L  Voluntary: 

Mastication. 
Respiration. 
Locomotion. 
2,  Involuntary: 
Cardiac. 
Smooth. 
The  function  of  muscles  is  contraction.    This  results  in  motion, 
oxidation,  reduction,  etc.,  with  consequent  formation  of  heat  and 
chemical  changes. 

Stimulation  may  result  in: 

1.  Greater  contraction. 

2.  More  prolonged  contraction. 

3.  The  ability  to  do  more  work. 

4.  Greater  chemical  activity. 

Drugs  may  cause  stimulation  or  depression  (1)  by  acting  directly 
on  the  muscle;  (2)  indirectly  through  the  nerve;  (3)  indirectly 
through  the  circulation. 

VOLUNTARY  MUSCLES. 

Why  one  group,  the  voluntary,  should  be  under  the  control  of 
the  will  and  another,  the  involuntary,  should  be  beyond  the  control 
of  the  will  cannot  be  answered.  The  fact  that  in  one  case,  volun- 
tary, the  mcjtor  nerves  arise  in  the  brain  anterior  to  the  fissure  of 
Rolando  and  that  the  effector  neurone  goes  direct  from  the  anterior 
portifni  of  the  cord  to  the  muscle,  does  not  explain  the  control  of 
this  group.  As  far  as  we  know,  one  set  should  be  as  much  under  the 
control  as  the  other.  Again,  why  one  set  may  be  paralyzed  by 
curara  and  another  by  atropin,  or  why  one  set  should  be  stimulated 
by  epincphriii  and  another  by  acetyl  cholin  or  pilocari)iii,  is  beyond 
our  grasp  at  the  present  time.  It  is  probably  due  to  chcnnical 
(iifl'<Terir('S  which  at  present  we  do  not  know. 


202  PHARMACOLOGY  OF  MUSCLES 

INVOLUNTARY  MUSCLES. 

GaskelP  subdivides  the  involuntary  muscles  according  to  their 
innervation  (based  on  their  development)  into  the  following  groups : 

1.  The  vascular  group,  which  includes  all  vessels,  and  is  supplied 
with  motor  fibers  from  the  sympathetic  alone — constrictor  and 
dilator. 

2.  The  dermal  or  ectodermal  group,  which  includes  those  muscles 
immediately  underneath  the  skin,  pilomotor,  muscles  of  sweat- 
glands,  etc.    The  motor  cells  all  belong  to  the  sympathetic. 

3.  The  endodermal  group,  which  lies  under  the  surface  of  the  gut 
and  is  innervated  by  both  enteral  parasympathetic  and  sym- 
pathetic. 

4.  The  urogenital-dermal  system  or  group,  which  is  derived  from 
the  segmental  duct.  This  includes  all  the  muscles  surrounding  the 
WoUfRan  and  Miillerian  ducts,  and  since  these  ducts  arise  from  the 
segmental  duct  it  may  be  called  the  segmental  duct  system  of 
involuntary  muscles.^  It  includes  the  muscles  of  the  Fallopian 
tubes,  uterus,  ureters,  vas  deferens,  bladder,  rectum  and  large 
intestine  or  all  muscles  innervated  by  the  lumbar  splanchnic  nerve 
through  the  inferior  mesenteric  ganglion.  Both  motor  and  inhibi- 
tory nerves  in  this  system,  according  to  Gaskell,  belong  to  the 
sympathetic  system.  The  innervation  is  not  reciprocal,  i.  e.,  not 
from  two  systems  of  nerves,  as  in  the  gut. 

5.  The  sphincter  muscles  of  the  gut,  bladder  and  urethra,  which 
receive  motor  fibers  from  the  sympathetic.  These  sphincter  muscles 
contract  under  the  influence  of  epinephrin — act  like  the  pilomotors 
— and  Gaskell  considers  they  have  a  similar  origin. 

6.  The  group  of  muscles  connected  with  the  adjustment  of  vision, 
which  has  a  reciprocal  innervation. 

According  to  the  reaction  to  drugs,  these  muscles,  therefore,  may 
be  placed  in  two  classes:  Groups  1,  2,  4  and  5  are  all  united  by  the 
sympathetic  nervous  system  and  contract  with  small  doses  of 
adrenalin.  Group  (3)  contracts  with  acetyl  cholin  and  is  known  as 
the  acetyl-cholin  group.  Gaskell  considers  that  both  motor  and 
inhibitory  nerve  cells  of  the  segmental  duct  system  belong  entirely 
to  the  sympathetic  system  and  are  not  in  any  way  connected  with 
the  enteral  fiystem.  He  does  not  use  the  modern  classification,  but 
essentially  the  same  thing.  He  classifies  the  involuntary  system 
into:    (1)  Sympathetic  or  bulbo,  and  (2)  enteral  or  sacral. 

1  The  Involuntary  Nervous  System,  1916. 

2  Gaskell:  The  Involuntary  Nervous  System,  p.  40. 


INVOLUNTARY  MUSCLES  203 

More  recent  work  has  shown  that  the  sacral  autonomic  system 
sends  motor  fibers  to  the  uterus,  rectum,  bladder,  anus  and  external 
genitals,  and  in  this  region  there  still  remains  much  uncertainty 
regarding  the  innervation  and  the  action  of  drugs.  The  pharma- 
cology of  the  muscles,  i.  e.,  the  direct  action  of  drugs  on  the  muscle 
is  less  important  than  the  pharmacology  of  the  nervous  mechanism 
regulating  muscular  activity. 

Gaskell's  classical  work  shows  the  necessity  for  further  investiga- 
tion in  the  pharmacology  of  this  region. 

General  proofs  that  a  drug  acts  directly  on  a  muscle  are:  1.  When 
the  action  is  direct  on  the  muscle  it  is  the  same  on  all  muscles  and 
not  as  in  the  case  of  adrenalin  which  acts  on  nerve-endings,  and 
causes  contraction  in  one  location  and  relaxation  in  another. 

2.  The  action  occurs  after  the  nerves  have  degenerated. 

3.  The  action  occurs  in  muscles  where  motor  nerves  do  not 
exist,  as  in  the  bloodvessels  of  the  lungs,  brain,  etc. 

While  the  direct  action  on  the  muscle  exists  in  many  cases,  the 
most  important  action  on  muscles  is,  as  a  rule,  through  the  nerves 
and  the  blood.     Drugs  may  stimulate  or  depress  muscle,  as  they 
influence  function. 
Drugs  which  act  directly  on  muscle: 

Caffein. 

Digitalis. 

Veratrin. 

Alcohol. 

Pituitrin. 

Barium  and  heavy  metals. 

Physostigmin. 

Aconitin. 

Saponin. 

Emetin. 

Cocain,  quinin,  etc. 

Classification  of  Drugs  Acting  on  Muscles. 

I. — Drugs  which  diminish  the  power  of  striated  muscle: 
Quinin. 
Chloral. 
Chloroform. 
Potassium  salts. 
Ammonium  salts. 
Lithium  salts. 


204  PHARMACOLOGY  OF  MUSCLES 

II. — Drugs  which  increase  the  power  of  striated  muscle  to  do  work: 

Alcohol. 

Veratrin. 

Barium. 

Calcium. 

Digitalis  bodies. 

Glycerin. 

Sugar. 

Caffein  compounds. 
Ill, —  Drugs  which  increase  the  irritability  of  striated  muscle. 

Physostigmin. 

Aconitin. 
IV. —  Drugs  which  depress  smooth  muscle: 

Nitrites. 

Organic  nitrates. 
V. —  Drugs  lohich  stimulate  smooth  muscle: 

Barium,  pituitrin. 
VI. —  Drugs  which  stimulate  cardiac  muscle: 

Barium. 

Caffein  bodies. 

Digitalis  bodies. 

Calcium  salts. 
VII. —  Drugs  which  depress  the  cardiac  muscle  directly: 

Potassium  salts  and  narcotics  of  the  aliphatic  series, 
especially  chlorin  compounds. 

Bile  salts. 

PITUITARY  EXTRACT,  LIQUOR  HYPOPHYSIS,  PITUITRIN, 
INFUNDIBULIN,  ETC. 

In  studying  this  drug  it  should  be  compared  with  epinephrin, 
digitalis,  ergot,  barium  and  the  nitrites. 

Experiment  I. — Inject  0.5  c.c.  of  liquor  hypophysis  into  the 
anterior  lymph  sac  of  a  frog  and  note  the  action. 

Experiment  II. — Arrange  a  frog  on  the  board  for  the  study  of  the 
circulation  through  the  web  of  the  foot  or  the  mesentery.  Make  a 
sketch  of  the  condition  of  the  vessels.  Inject  0.5  c.c.  liquor  hypo- 
physis into  the  anterior  lymph  sac  and  watch  closely  for  some 
minutes  for  any  change  that  may  occur  in  the  circulation.  After 
ten  minutes  observe  at  fifteen-minute  intervals  for  two  hours. 

Experiment  III. — Action  of  Liquor  Hypophysis  on  the  Heart. — 
(a)  Take  a  tracing  of  the  contractions  of  the  heart  of  a  frog  or  turtle 


PITUITARY  EXTRACTS  AND  LIQUOR  HYPOPHYSIS     205 

by  the  suspension  method.  Test  the  action  of  vagus  stimulation. 
Irrigate  with  a  1  to  5  solution  of  liquor  hypophysis.  After  some  time 
again  test  the  efficiency  of  vagus  stimulation. 

(h)  Irrigate  with  a  0.1  per  cent,  atropin  sulphate  until  the  vagus 
action  is  eliminated  and  again  try  the  action  of  liquor  hypophysis. 


^^'^^ 


Fig.  4.'i. — Preparation  for  examining  the  circulation  in  the  frog's  mesentery.     The 
preparation  can  be  placed  under  a  microscope. 


Experiment  IV. — Repeat  Experiment  III,  using  atropin  before 
liquor  hypophysis.     (Section  h,  III.) 

Experiment  V. — Prepare  turtle  heart  strips,  and  when  these  are 
beating  rhythmically,  add  lifpior  hypophysis,  drop  by  drop,  and 
note  the  action. 

Experiment  VI. — Action  of  Lie/nor  Ilyjjophysi.s  on  the  Heart,  Respi- 
ration,  I'lipila  and  A' /V/z/r^/.v.—  Anesthetize  a  dog  and  pre])are  for 
blofjd-pressurc  and  respiration  tracings.  Insert  catheters  in  the 
uterus  or  bladder  for  measuring  the  flow  of  urine.  Note  the  condi- 
tion of  the  [)upil.  Insert  a  cannula  in  the  femoral  vein  for  injection. 
Isolate  and  test  the  vagus  resj)onse  to  stimulation. 

1.  Take  normal  tracing. 


206  PHARMACOLOGY  OF  MUSCLES 

2.  Inject  2  c.c.  of  a  1  to  5  solution  of  liquor  hypophysis  into  the 
femoral  vein.  Repeat  if  necessary  until  definite  results  are  obtained. 
Make  a  record  of  the  change. 

3.  When  the  action  is  marked,  stimulate  the  vagus. 

4.  Inject  1  c.c.  of  1  to  10,000  epinephrin  and  compare  its  action 
at  all  points  with  liquor  hypophysis. 

5.  Repeat  2.  When  satisfied  with  the  comparison,  isolate  a  loop 
of  the  intestine  and  make  a  record  of  the  intestinal  movements  in 
the  usual  way. 

6.  Inject  2  c.c.  of  1  to  5  solution  of  liquor  hypophysis. 

7.  When  definite  action  is  obtained  in  6,  inject  1  c.c.  of  1  to  10,000 
epinephrin. 

8.  Inject  slowly  5  c.c.  of  0.5  per  cent  barium  chloride. 

The  Main  Action  of  Liquor  Hypophysis. — 1.  An  action  on  smooth 
muscle  structures  such  as  the  heart,  vessels,  bladder,  uterus,  intes- 
tines, seems  to  bear  no  relation  to  innervation,  since  the  pulmonary 
and  coronary  vessels  constrict  decidedly. 

2.|It  increases  oxidation  and  metabolism  and  stimulates  the 
growth  of  skeletal  and  connective  tissues. 

3.  Excessive  doses  cause  nervous  symptoms. 

4.  It  alters  the  susceptibility  to  many  poisons  (Hunt's  nitril 
reaction)   increases  some  (morphin)  diminishes  others  (nitrils). 

5.  It  acts  as  a  hormone  in  the  development  and  action  of  other 
glands,  the  kidneys  and  sexual  especially.  In  studying  this  drug, 
watch  for  evidences  for  or  against  these  statements. 

Preparation  of  Uterine  Segments  for  the  Study  of  the  Action  of 
Infundibular  Extracts. — ^The  uterus  of  a  guinea-pig  or  cat  is  the  most 
suitable,  but  the  uterus  of  any  animal  will  answer.  Virgin  or  non- 
pregnant uteri  give  the  best  results.  To  remove  the  uterus  from  the 
body  the  animal  is  bled  to  death  without  an  anesthetic.  Anesthesia 
inhibits  or  prevents  the  uterine  movements  to  a  considerable  extent. 
Shock  also  prevents  uterine  movements  and  must  be  avoided.  It 
is  best  to  decapitate  the  animal  quickly  with  a  sharp  instrument. 
Then  quickly  remove  the  uterus  and  handle  it  with  special  care. 
Do  not  take  it  up  in  the  fingers  but  handle  with  warm  forceps  and 
cut  with  sharp  scissors.  Place  it  immediately  in  a  vessel  of  warm 
aerated  saline.  Remove  segments  for  testing  contractions  by  cutting 
under  the  saline  bath.  Use  segments  about  2  cm.  in  length.  Success 
with  uterine  strips  demands  that  they  be  carefully  handled  at  the 
correct  temperature  and  that  they  be  adequately  aerated. 

Experiment  VII. — Action  of  Liquor  Hypophysis  on  the  Uterus. — (a) 
Prepare  a  uterine  segment  for  recording  contractions.     When  it  is 


PITUITARY  EXTRACT  AND  LIQUOR  HYPOPHYSIS      207 

contracting  rhythmically  add  0.01  c.c.  of  liquor  hypophysis  and 
note  the  result.  If  this  does  not  cause  an  increase  in  the  con- 
traction, increase  the  amount  added  until  it  does.  The  actual  result 
will  vary  with  different  uteri  and  the  result  can  be  judged  only  by 
comparing  the  effect  of  the  solution  added,  with  the  effect  of  a 
standardized  preparation.     (See  Method  of  Standardizing.) 

(6)  Study  the  action  of  liquor  hypophysis  on  the  uterus  in  situ 
by  Barbour's  method;   inject  the  drug  into  the  femoral  vein. 

Experiment  VIII. — Standardization  of  Pituitary  Extracts. — The 
action  on  the  blood-pressure  as  well  as  the  action  on  the  uterus 
has  been  advocated  as  a  means  of  standardizing  pituitary  extracts. 
The  blood-pressure  method  is  as  follows: 

0.05  c.c.  of  standard  pituitary  should  give  an  average  rise  in  the 
blood-pressure  of  30  mm.  Hg.  when  injected  into  the  femoral  vein 
of  a  dog  8  to  12  kilos  in  weight.  The  extracts  found  on  the  market 
var}'  from  10  to  20  per  cent,  extracts  of  the  gland.  But  some  10  per 
cent,  extracts  are  as  strong  as  other  20  per  cent.,  hence  the  need  of 
standardization.  If  the  preparation  tested  shows  a  blood-pressure 
rise  of  less  than  24  mm.  Hg.  the  dose  should  be  increased,  while 
if  the  rise  is  more  than  40  mm.  Hg.  the  amount  injected  should  be 
lessened.  The  objections  to  the  blood-pressure  method  of  stan- 
dardizing pituitary  extracts  are: 

1.  In  clinical  work  pituitary  extract  is  used  almost  entirely  for 
its  action  on  the  uterus.  The  action  on  the  blood-pressure  may  bear 
no  relation  to  the  action  on  the  uterus,  since  pituitary  extract  con- 
tains two  principles,  a  pressor  and  a  depressor.  The  pressor  prin- 
ciple is  easily  destroyed.    Both  principles  act  on  the  uterus. 

2.  Repeated  observations  cannot  be  made  on  the  same  animal, 
since  liquor  hypophysis  is  less  easily  oxidized  in  the  body  than 
epinephrin  and  cannot,  like  this,  be  repeatedly  injected  with  the 
same  effect. 

3.  The  blood-pressure  is  a  rather  stable  thing  and  not  readily 
influenced.  Great  variations  in  the  strength  of  solutions  of  the 
pituitary  body  may  obtain,  and  this  method  will  fail  to  show  it. 
Roth,  however,  found  that  commercial  pituitary  extracts  vary  less 
in  blood-pressure  effects  than  in  their  effects  on  the  uterus. 

4.  \^ariations  in  the  depth  of  anesthesia  cause  marked  changes 
in  the  blood-pressure  rise. 

Uterine  Method  of  Standardization  of  Pituitary  Extract. — P'or  every 
gram  of  the  fresh  {posterior  lobe,  finely  ground  and  minced,  5  c.c. 
(jf  0.1  per  cent,  acetic  acid  is  added  and  sufficient  water  to  make 
1  c.c.  of  water  for  each  gram  of  the  gland.    1'he  mixture  is  boiled 


208  PHARMACOLOGY  OF  MUSCLES 

for  ten  minutes,  filtered  and  made  up  to  10  c.c.  One  c.c.  of  this 
filtrate  represents  0.1  gram  of  the  fresh  gland.  Dried  material 
may  be  used  if  calculated  in  terms  of  fresh  material.  Twenty  parts 
of  dried  material  are  equal  to  100  parts  of  fresh.  On  autoclaving 
to  sterilize  the  solution  loses  some  of  its  strength,  but  after  that  it 
will  keep  indefinitely.  A  solution  of  this  kind  may  be  used  as  a 
standard.  The  average  of  solutions  prepared  in  this  way  when 
diluted  20,000  times  should  have  the  same  activity  on  the  isolated 
uterus  of  the  virgin  guinea-pig  as  a  1  to  2,000,0000  solution  of  beta- 
amino-azolyl-ethylamin  hydrochloride,  when  tested  as  directed  by 
the  U.  S.  Hygienic  Laboratory  Bulletins  Nos.  100  and  109.  This 
method  is  essentially  that  given  in  Experiment  VII  above. 

NITRITES. 

The  main  action  of  the  nitrites  on  the  heart  and  circulation  are: 

1 .  The  vessels  are  dilated  through  loss  of  tone,  due  to  direct  action 
on  the  muscle  of  the  vessel.  The  action  is  on  the  vessel  wall,  since 
it  bears  no  relation  to  innervation,  and  the  coronaries  and  pul- 
monaries  dilate. 

2.  The  rate  of  the  heart  is  accelerated,  due  to  the  low  pressure 
lessening  the  effect  of  the  vagus. 

3.  The  formation  of  methemoglobin. 

VERATRIN. 

Veratrin  is  but  little  used  in  therapeutics.  It  has  several  definite 
actions  which  should  be  studied  and  compared  with  other  drugs, 
especially  barium  chloride  and  aconitin. 

The  main  actions  of  veratrin  are: 

1.  An  aconitin-like  action  on  the  sensory  nerves. 

2.  A  peculiar  characteristic  stimulation  of  the  muscle  substance, 
which  leads  to  a  persistence  of  muscle  tone,  with  prolonged 
relaxation. 

This  action  is  a  stimulation  because : 

1.  Fatigue,  or  fatigue  products  like  KCl,  or  lactic  acid  prevents  it. 

2.  The  muscle  under  veratrin  will  do  more  work. 

Experiment  I. — Make  a  2  per  cent,  oleatum  veratrinse  by  tritu- 
rating 2  grams  of  veratrin  in  5  c.c.  of  olive  oil  in  a  mortar.  Warm 
the  mortar  and  add  50  c.c.  of  oleic  acid.  Continue  stirring  until  the 
veratrin  is  dissolved,  then  add  45  c.c.  of  olive  oil.  Take  2  c.c.  of 
this  and  rub  thoroughly  over  the  course  of  a  nerve.  What  are  the 
symptoms?    This  is  sometimes  used  in  neuralgias. 


QUININ 


209 


Experiment  II. — Inject  0.5  c.c.  of  0.01  per  cent,  veratrin  into  the 
abdominal  lymph  sac  of  a  frog.  Compare  this  with  a  normal  animal. 
Watch  for  one  hour. 

Experiment  III. — Count  pulse  and  respiration  in  each  animal  and 
give  a  cat,  dog  and  rabbit  0.5  c.c.  per  kilo  body  weight  of  0.1  per 
cent,  veratrin  hypodermically.  Note  the  symptoms  and  changes 
from  normal. 


Ji 


Fig.  44. — Tracings  of  muscular  contractions  from  the  gastrocnemius  of  the  frog 
a,  normal;  h,  three  successive  contractions  taken  at  intervals  of  one  minute,  five 
minutes  after  the  injection  of  veratrine.  The  contraction  is  higher  and  much  more 
prolonged  than  in  a,  and  the  lever  returns  very  slowly  to  the  base  line.      (Cushny.) 

Experiment  IV.— Ligate  one  leg  of  a  frog  so  as  to  shut  off  the 
circulation.  Inject  0.5  c.c.  of  0.1  per  cent,  veratrin  into  the  ab- 
dominal lymph  sac.  After  thirty  minutes  prepare  the  muscle  of 
each  leg  for  a  single  contraction  record.  What  is  the  difference  in 
the  normal  and  veratrinized  muscle?    Tracings. 

Experiment  V. — Prepare  a  dog  for  blood-pressure  and  respiration 
tracings.  Place  a  cannula  in  the  femoral  vein  for  injection;  take 
a  normal  tracing  and  inject  1  c.c.  of  0.1  per  cent,  veratrin  every 
five  minutes  until  the  animal  dies. 

Experiment  VI.— Veratrin  on  the  turtle  heart  strips.  Take 
nfjrmal  tracings,  mea.sure  the  volume  of  the  fluid  in  which  the  strip 
is  contracting  and  take  tracings  when  this  contains  0.0001,  0.0003 
and  O.OWf)  per  cent,  veratrin. 


QUININ. 

Qiiiiiin  is  a  general  [)rot()plasinic  jKji.son,  with  a  specific  action  on 
tlie  malarial  plasniodium.     It  has  also  an  antii)yretic  action. 
14 


210  PHARMACOLOGY  OF  MUSCLES 

Experiment  I. — (a)  Action  on  Yeast  Fermentation. — Make  up  a 
10  per  cent,  solution  of  glucose  in  1  per  cent.  NaCl  and  place  in  a 
fermentation  tube.    Inoculate  with  yeast. 

(b)  Make  a  10  per  cent,  solution  of  glucose  in  1  per  cent,  quinin 
bisulphate.  Inoculate  with  yeast  and  place  both  samples  in  an 
incubator  at  40°  C.  and  compare  the  rate  of  fermentation. 

Experiment  II. — Inject  1  c.c.  of  0.1  per  cent,  quinin  bisulphate 
into  the  anterior  lymph  sac  of  frog  and  place  in  a  quiet  place. 
Count  the  rate  of  the  lymph  heart  and  note  changes  in  the  general 
reactions  of  the  animal. 

Experiment  III. — Action  of  Quinin  on  White  Corpuscles. — Pith  a 
frog;  pin  to  a  cork  plate  and  expose  the  intestine  with  mesentery 
intact  for  observation  of  the  circulation  with  a  microscope.  Isolate 
a  field  in  which  one  can  see  the  circulation.  Look  especially  at  the 
white  cells  and  note  their  relation  to  the  vessel  wall.  When  a  nor- 
mal tracing  has  been  obtained,  inject  1  c.c.  of  0.5  per  cent,  quinin 
bisulphate  into  the  anterior  lymph  sac  and  watch  carefully  for 
changes  in  the  behavior  of  the  white  cells. 

Experiment  IV. — Action  of  Quinin  on  the  Frog  or  Turtle  Heart. — 
Take  a  tracing  by  the  suspension  method.  Irrigate  the  heart  slowly 
with  0.05  per  cent,  quinin  bisulphate.  After  thirty  minutes  use 
0.1  per  cent. 

Experiment  V. — Quinin  on  the  Heart  and  Respiration  of  a  Mammal. 
— Count  the  respiration  and  heart-rate  of  a  dog.  Inject  5  c.c.  of 
0.2  per  cent,  quinin  bisulphate  into  the  femoral  vein  without  an 
anesthetic  and  record  changes.  Repeat  with  larger  doses  if  thought 
advisable. 

Experiment  VI. — Anesthetize  a  dog.  (a)  Prepare  for  blood-pres- 
sure and  respiration  tracings.  Isolate  and  cut  the  right  vagus  and 
prepare  for  stimulation  of  the  central  and  peripheral  ends.  Place 
a  cannula  in  the  femoral  vein. 

(6)  Take  normal  tracings  and  stimulate  each  end  of  the  vagus 
separately. 

(c)  Inject  2  c.c.  of  0.1  per  cent,  quinin  bisulphate  into  the  femoral. 
Study  changes  of  the  action  on  the  vagus. 

{d)  Repeat  (c)  with  increasing  doses  until  definite  acti6n  is 
obtained. 

Experiment  VII. — Quinin  Urea  Hydrochloride. — Inject  an  area  of 
a  dog's  leg  with  1  per  cent,  quinin  urea  hydrochloride.  'Compare 
the  efficiency  of  this  with  0.01  per  cent,  cocain  hydrochloride.  In 
three  minutes  after  the  injections,  determine  whether  or 'not  the 
areas  are  sensitive  to  pain. 


CALCIUM,  BARIUM  AND  MAGNESIUM  SALTS  211 

Experiment  Vni.— Take  5  grains  of  quinin  bisulphate  in  water. 
After  one  hour  collect  the  urine  and  apply  the  Thalleoquin  test  as 
follows: 

(a)  To  about  10  c.c.  of  the  urine  add  3  c.c.  fresh  bromine  or  chlorin 
water.    Then  add  gradually  an  excess  of  ammonium  hydroxide,  or 

(b)  Add  a  drop  or  two  of  ammonia  to  the  urine  and  extract  with 
ether.  Evaporate  the  ether,  add  a  drop  of  5  per  cent.  HCl  and  dis- 
solve the  residue  in  water.    Test  as  in  (a). 

Experiment  IX. — Heat  a  piece  of  cinchona  bark  in  a  dry  test-tube. 
If  quinin  is  present  a  carmine  colored  vapor  will  be  given  off. 

CALCIUM,  BARIUM  AND  MAGNESIUM  SALTS. 

Experiment  I.— Action  on  the  Frog's  Heart. — Excise  the  hearts  of 
six  frogs  and  place  in  watch-glasses.  Note  how  long  they  continue 
■to  beat  in  the  following  solutions. 

1.  Ringer's  solution. 

2.  Ringer's  without  Ca. 

3.  Ringer's  without  K. 

4.  XaCl  0.8  per  cent. 

5.  Distilled  \vater. 

6.  0.7  XaCl  in  0.1  per  cent,  sodium  oxalate.    Explain  results. 
Experiment  II.— Prepare  a  dog  for  blood-pressure  and  respiratory 

tracing. 

(a)  Slowly  inject  sodium  oxalate  until  the  heart  begins  to  fail. 
Now  inject  0.1  per  cent.  CaCl2. 

(h)  Inject  1.0  c.c.  of  1  per  cent.  KCl  and  repeat  if  necessary 
until  the  heart  is  markedly  depressed.  Then  repeat  the  injection 
of  CaCl2. 

(c)  Isolate  a  loop  of  intestine  for  observation  or  for  tracing  of 
movement.  Inject  sloAvly  into  the  femoral  vein  5  c.c.  of  0.2  per  cent. 
BaClz;  watch  the  blood-pressure  and  condition  of  the  intestine. 
When  the  intestine  contracts  markedly,  inject  about  10  c.c.  CaClo 
slowly  and  observe  results.  Place  a  few  drops  of  warm  CaCl 
directly  on  the  gut. 

Experiment  III,- -Calcium  and  Magnesium  Antagonism.— CAve  a 
rabbit  a  subcutaneous  injection  of  5  c.c.  of  25  per  cent.  MgSO^  per 
kil(j.  In  about  thirty  minutes  anesthesia  follows.  Now  rub  a  little 
toluol  on  the  veins  of  the  ear  to  dilate  them.  Clamp  the  vein  with 
a  bulldog  clamp  and  inject  into  the  vein  slowly  about  8  to  10  c.c.  of 
y,  ]>iT  cent,  calcium.  What  is  the  efl'ect?  Rabbits  are  very  easily 
killed  by  air  embolism. 


212  PHARMACOLOGY  OF  MUSCLES 

Experiment  IV. — Prepare  several  turtle  heart  strips.  Place  1  (a) 
in  normal  saline.  When  it  is  beating  rhythmically  add  a  sufficient 
quantity  of  barium  chloride  to  make  the  solution  0.01  per  cent. 

(b)  To  number  (2)  in  the  same  way  add  sufficient  CaCl2  to  make 
it  0.03  per  cent.  When  there  is  marked  action  on  the  beat  exchange 
(a)  and  (6).  If  an  exchange  cannot  be  made  conveniently  change 
the  solution  in  both. 


CHAPTER   XXI. 

PHARMACOLOGY  OF  THE  LYMPHATICS. 

Lymph  is  the  colorless  fluid  which  fills  the  lymphatic  vessels  and 
surrounds  the  tissue  elements.  The  movement  is  from  the  tissue 
to  the  veins  and  this  movement  is  due  to  (1)  the  difference  in  pres- 
sure of  the  lymph  at  its  origin  and  the  pressure  in  the  larger  veins, 
(2)  to  the  movement  of  the  muscles,  etc.,  (3)  to  the  movements  of 
respiration,  and  (4)  in  certain  animals,  notably  the  frog,  it  is  due 
to  the  rhythmic  action  of  lymph  hearts. 


Fig.  45. — Po.sterior  lymph  hearts  in  the  frog.  The  beating  of  these  hearts  will 
facilitate  the  spread  of  a  drug  in  the  frog  after  the  blood  heart  has  been  removed, 
L,  posterior  lymph  hearts;  GL,  gluteus  muscles;  7C',  iliococcygeus;  P,  pyriformis;  R. 
rectus;  VE,  va.stus  externus.     (After  Ecker.) 


The  physiology  of  lymph  formation  is  not  settled,  therefore  the 
pharmacology  must  be  somewhat  incomplete.  Certain  facts  are 
definite,  but  depending  on  whether  we  consider  the  lymph  a  secre- 
tion or  a  filtration  the  exjjlaiiation  will  vary.  Ludwig  taught  that 
lymph  is  formed  by  filtration,  and  in  minor  degree  by  dill'usion. 

Heidenhain  believed  that  lymph  is  secreted  by  the  cai)illary 
epithelium. 

Drugs  that  cause  a  flow  of  lynijih  are  called  lyinj)hagogues. 
Heidenhain  classifies  these: 


214  PHARMACOLOGY  OF  THE  LYMPHATICS 

Class  I:  Peptone. 

Leech  extract. 

Extract  of  crayfish  muscle. 

Egg  albumen. 

Protein  substances,  these  increase  the  amount,  specific  gravity 
and  the  total  solids  of  the  lymph — probably  due  to  injury  of  the 
vessels — inflammation. 

Class  II :  Salts,  sugar,  etc.  Crystalline  substances  that  increase 
the  volume  but  cause  a  more  watery  lymph. 

Experiment  I. — Anesthetize  a  dog  and  record  arterial  pressure, 
insert  a  cannula  into  the  thoracic  duct  and  measure  the  flow  of 
lymph.  Now  inject  slowly  5  c.c.  of  a  5  per  cent,  peptone  solution 
and  note  the  changes  in  lymph  flow  and  blood-pressure.  Repeat 
until  definite  action  is  obtained. 

Experiment  II. — Repeat  Experiment  I,  using  potassium  iodide 
sugar,  etc.    Test  the  lymph  for  presence  of  the  drugs  used. 

Experiment  III. — ^Test  the  effect  of  pilocarpin  and  atropin  on  the 
flow  of  lymph  as  in  the  previous  experiment. 

An  extract  from  the  lymph  glands  of  animals  has  been  employed 
in  exophthalmic  goiter,  lymphadenoma  and  other  glandular  swell- 
ings, but  the  results  are  not  thought  to  be  of  any  permanent  value. 

From  a  practical  standpoint  the  flow  of  lymph  must  be  influenced 
through  the  factors  that  are  most  concerned  in  its  circulation,  viz. : 

1.  The  circulation  of  the  blood. 

2.  The  condition  of  the  muscles. 

3.  Respiration. 

The  fact  that  the  atropin  or  pilocarpin  have  no  influence  on  the 
flow  of  lymph,  indicates  that  it  is  not  a  secretion. 


CHAPTER   XXII. 

GENERAL  PROTOPLASM  POISONS  AND 
MISCELLANEOUS. 

HYDROCYANIC  ACID. 

Hydrocyanic  acid  is  a  general  protoplasmic  poison.  It  is  classi- 
fied by  Loew  a  "substituting"  poison  because  it  reacts  with  the 
aldehyde  group  forming  substitution  products.  The  nature  of  the 
combination  is  so  strong  that  it  is  fatal.  It  is  for  this  reason  a  gen- 
eral protoplasmic  poison.     The  main  actions  of  the  cyanides  are: 

1.  A  destructive  action  on  enzymes. 

2.  Primary  stimulation  and  paralysis  of  the  nerve  and  medullary 
centers. 

3.  A  paralysis  of  the  oxidative  processes  in  the  muscle. 

4.  An  action  on  the  blood-formation  of  methemoglobin  and 
cyanhemoglobin?     (See  Fig.  55,  page  239.) 

Experiment  I. — Drop  1  c.c.  of  5  per  cent.  KCN  solution  into  the 
mouth  of  a  small  cat.    Note  carefully  the  symptoms. 

Experiment  II. — Count  the  heart-beat  and  respiration  of  a  dog 
and  inject  intravenously  1  c.c.  of  1  per  cent.  XaCN  or  KCN. 
Record  results. 

Experiment  in. — Action  of  the  Cyanides  on  Respiration,  Blood- 
pressure,  and  Blood  and  Oxycjen  Consumption. — (a)  Give  a  dog  a 
hypodermic  injection  of  2  c.c.  of  3  per  cent,  morphin  sulphate. 

(6)  In  thirty  minutes  anesthetize  with  ether  and  prepare  for  blood- 
pressure  and  respiration  tracings  and  measure  the  exhaled  air  with 
a  spirometer.     Place  a  cannula  in  the  femoral  vein  for  injections. 

(c)  Take  normal  tracings  and  measurements. 

id)  Inject  1  c.c.  of  0.1  per  cent,  sodium  cv'anide  per  kilo.  If 
there  is  a  noticeable  effect,  measure  the  change  in  the  ex])ire(l  air. 

(e)  Repeat  with  double  the  dose  of  the  cyanide. 

(j)  When  aspliyxial  symptoms  become  marked,  examine  the  blood 
microscopi(;ally  and  with  the  spectroscope. 

ig)  Take  0.5  c.c.  of  blood  and  test  its  action  on  hydrogen  peroxide 
as  in  the  Ix'ginning  f)f  the  experiment. 

ill)  llydrocsiuiic  acid  is  siij)j)ose(i  to  com})ine  with  loosely-bouiid 
sulphur  ill   proteins  to  form   IISCX,  which   is  not   nearly  so  toxic 


216     GENERAL  PROTOPLASM  POISONS  AND  MISCELLANEOUS 

as  HCN.  For  this  reason  sulphides  have  been  advised  as  antidotes 
in  cyanide  poisoning. 

(i)  When  the  symptoms  of  asphyxiation  are  marked,  run  into  the 
femoral  vein  1  c.c.  of  5  per  cent,  sodium  sulphide  or  calcium  sul- 
phide. Run  this  in  slowly  as  sulphides  are  also  toxic.  Repeat  the 
sulphide  injection  if  necessary. 

(j)  If  the  animal  shows  a  return  toward  normal,  make  complete 
records. 

(k)  Repeat  the  sulphide  injection  if  it  is  thought  advisable. 

Collect  urine  at  the  end  of  each  experiment  with  the  cyanides 
and  test  for  sugar. 

ACIDS,  ALKALIES  AND  CORROSIVES. 

Experiment  I. — Prepare  an  animal  for  blood-pressure  and  respira- 
tion tracings.  Insert  a  cannula  in  the  femoral  vein  for  injection 
from  a  burette. 

(a)  Take  normal  tracing. 

(6)  Inject  slowly  until  symptoms  of  marked  depression  are 
apparent,  ^g-  HCl  or  any  other  acid. 

(c)  When  respiration  or  heart  shows  signs  of  collapse,  quickly 
inject  the  same  amount  of  y^  Na2C03. 

(d)  Repeat  (6)  and  (c).  If  animal  is  still  living,  use  for  one  of 
the  following  experiments. 

Experiment  II. — Corrosire  Action  of  Acids  and  Alkalies. — These 
experiments  should  be  carried  out  on  animals  that  have  been  used 
for  some  other  work,  as  it  is  not  necessary  to  waste  animals  for  these 
experiments  alone. 

Respiration  and  blood-pressure  tracings  should  be  taken  at  the 
same  time.    The  animals  should  be  deeply  anesthetized. 

Inject  50  c.c.  of  the  following  solutions  through  a  stomach  tube, 
and  after  thirty  to  sixty  minutes  remove  the  stomach  with  the 
esophagus  and  the  upper  part  of  the  small  intestine.  Spread  on  a 
white  paper  or  plate  for  comparison. 

(a)  50  c.c.  NaOH,  40  per  cent. 

(b)  50  c.c.  NH4OH,  concentrated. 

(c)  50  c.c.  HNO3,  concentrated. 

(d)  50  c.c.  HCl,  concentrated. 

(e)  50  c.c.  H2SO4,  concentrated. 
(/)   50  c.c.  phenol,  95  per  cent. 

(g)  50  c.c.  phenol  plus  95  to  100  c.c.  glycerin. 
(h)  50  c.c.  cresol. 


SULPHIDES  217 

(0    50  c.c.  picric  acid  concentrated  in  water. 
(j)    50  c.c.  acetic  glacial. 
(A')  50  c.c.  phosphoric,  50  per  cent. 
(/)    50  c.c.  HgCla,  0.1  per  cent. 
Experiment  III. — Set  up  four  fermentation  tubes  with  10  per  cent, 
glucose.     Inoculate  with  yeast.    Keep: 

1.  For  control. 

2.  Make  slightly  acid  with  HCl. 

3.  Make  weakly  alkaline  with  NaaCOs. 

4.  Make  strongly  alkaline  with  NaOH. 
Compare  the  rate  of  fermentation  at  40°  C. 

Experiment  IV. — Put  about  10  grams  of  muscle  or  glandular  tissue 
in  each  of  seven  test-tubes  and  cover  with: 

1.  Concentrated  H2SO4. 

2.  Concentrated  HCl. 

3.  Concentrated  NaOH. 

4.  Concentrated  acetic  acid. 

5.  Phenol  95  per  cent. 

6.  Concentrated  HNO4. 

7.  Tincture  iodin. 

After  fifteen  minutes  wash  off  the  chemical  and  compare  with  the 
original. 

SULPHIDES. 

The  sulphides  are  readily  absorbed  and  excreted  by  the  lungs. 

Experiment  I. — Compare  this  with  ammonia.  Anesthetize  a  dog. 
Insert  a  tracheal  cannula.  Take  blood-pressure  tracing  from  the 
carotid  and  respiratory  tracing  from  the  abdomen.  Inject  slowly 
1  per  cent,  sodium  sulphide  or  ammonium  sulphide  into  the  femoral 
vein  and  hold  a  piece  of  paper  moistened  with  silver  nitrate  or  lead 
acetate  at  the  tracheal  cannula.  Note  the  time  necessary  to  detect 
the  excretion  of  the  sulphide. 

Experiment  11. — Repeat  with  calcium  sulphide.  Determine  the 
toxic  dose  and  the  cause  of  death.  This  has  been  advised  in  mercuric 
chloride  poisoning. 

Experiment  III. — Action  of  Sulj)hides  on  Yeast  Fermentation. — 
In  a  series  of  fermentation  tubes  containing  10  ])er  cent,  cane  sugar 
containing  yeast  add: 

1.  0.01  per  cent,  sodium  or  potassiinn  sulphide. 

2.  0.05  per  cent,  sodium  or  potassium  sulphide. 

3.  0.1  per  cent,  sodium  or  potassium  sul})hide. 

4.  Control. 

What  is  the  effect  ou  fermentation  at  40°  C? 


218     GENERAL  PROTOPLASM  POLSONS   AND   MISCELLANEOUS 

Experiment  IV. — Coat  the  hairy  surface  of  the  arm  with  a  layer 
of  CaS,  prepared  by  rmuiing  HoS  into  milk  of  lime,  and  in  a  few 
minutes  scrape  it  off  with  a  scalpel.    What  is  the  result? 

Experiment  V. — Examme  the  chest  of  an  anesthetized  animal  with 
a  stethoscope.  Allow  to  mhale  the  fumes  of  dilute  H2S.  Continue 
the  inhalation  until  symptoms  of  edema  take  place.  State  findings 
and  give  explanation. 


OXALATES  AND  FLUORmES. 

Experiment  I. — (a)  Put  a  pinch  of  powdered  sodium  or  potassium 
oxalate  into  a  test-tube.  Add  5  c.c.  of  blood  and  shake.  Compare 
the  clotting  time  of  oxalated  blood  with  normal  blood. 

(b)  Use  potassium  or  sodium  fluoride  as  m  (a). 

Experiment  II. — (a)  Anesthetize  a  dog  and  prepare  for  blood- 
pressure  and  respiratory  tracings.  Inject  slowly  into  the  femoral 
vein  0.1  per  cent,  sodium  oxalate.  When  depression  is  marked 
inject  1  per  cent,  calcium  chloride  slowly.  Oxalates  are  general 
protoplasmic  poisons,  because  they  precipitate  calcium  salts  and 
calcium  is  necessary  to  the  life  of  protoplasm. 

(b)  Use  0.1  per  cent,  potassium  fluoride  as  in  («). 


IODIDES. 

1.  Excretion. — Take  0.5  gram  KI  in  a  capsule.  After  fifteen 
minutes  collect  about  5  c.c.  saliva,  add  a  few  drops  of  H2SO4  and  an 
equal  volume  of  1  per  cent,  sodium  nitrite  and  shake  with  5  c.c. 
of  cliloroform.  If  I  is  present  it  will  dissolve  the  chloroform  with  a 
violet  color.  Repeat  every  five  minutes  until  I  is  detected.  Then 
again  m  twenty-four  hours.    Test  the  urine  in  the  same  way. 

2.  Twelve  students  in  groups  of  six  each  should  study  the  absorp- 
tion of  iodides  from  the  gastro-intestinal  tract  as  follows:  Six  study 
the  time  of  absorption  and  excretion  on  an  empty  stomach,  i.  e., 
11  A.M.  or  4  P.M.,  and  the  other  six  immediately  after  a  midday 
meal.  Compare  the  average  time  of  absorption  as  manifested  by 
the  above  tests.  The  results  with  the  iodides  will,  in  general,  hold 
good  for  the  other  drugs.  What  is  the  philosophy  of  giving  drugs 
sometimes  before,  sometimes  after  meals? 

3.  Many  of  the  uses  and  supposed  benefits  of  the  iodides  can  be 
studied  only  in  clinical  cases.    Their  mode  of  action  is  still  obscure. 


HEAVY  METALS  219 

HEAVY  METALS. 

These  have  a  local  and  a  general  action.  The  local  action  is 
due  to  their  combining  with  the  proteins.  The  general  action 
appears  only  after  absorption  and  is  manifest  mainly  on  the  kidney, 
circulation,  and  central  nervous  system. 

1.  Test  the  action  of  a  few  drops  of  5  per  cent.  AgNOa,  HgCb, 
Fe2Cl6,  CuS04,  Pb (€211302)2  and  ZnS04  on  a  solution  of  egg  white 
or  blood  serum. 

2.  Give  a  dog  5  mg.  per  kilo  of  mercuric  chloride.  Watch  this 
animal  for  several  days  or  until  he  dies.  Note  especially  heart-rate, 
nervous  symptoms  and  the  action  on  the  kidneys  as  manifested  by 
the  urine  and  by  the  postmortem. 

3.  Action  on  yeast:  Shake  a  cake  of  yeast  in  500  c.c.  of  2  per  cent, 
dextrose.  Fill  a  series  of  fermentation  tubes.  Keep  one  for  control 
and  to  the  others  add  0.1  c.c.  and  1  c.c.  of  the  solution  in  Experi- 
ment I.    Note  the  results  in  thirty  minutes  and  in  twenty-four  hours. 

Local  Action. — Heavy  metals  unite  with  proteins  to  form  pro- 
teinates. 

The  proteins  may  play  the  part  either  of  acid  or  base. 

These  salts  are  not  true  chemical  compounds,  i.  e.,  they  are  not 
of  definite  composition.  The  amount  of  the  heavy  metal  in  the 
precipitate  varies.  The  precipitating  action  on  proteins  causes  the 
heavy  metals  to  act  as  astringents,  and  it  also  explains  the  vomiting 
caused  by  the  heavy  metals.  As  astringents  they  may  act  in  three 
ways: 

1.  By  the  formation  of  albuminates,  with  the  liberation  of  free 
acids,  and  the  acid  also  causing  some  astringent  action. 

2.  The  metal  may  be  absorbed  locally  and  so  constrict  the  local 
vessels. 

3.  The  insoluble  salts,  like  bismuth  subnitrate,  may  cover  and 
protect  the  surface  mechanically. 

General  Action. — The  general  action  of  the  heavy  metals  is  seen 
only  after  prolonged  ingestion. 

The  general  symptoms  and  actions  of  the  heavy  metals  differ 
mainly  in  the  rate  of  absorption.  There  is  little  difference  in  the 
toxicity  of  arsenic  and  iron  when  injected  into  the  blood. 

Mercur}'  is  the  only  heavy  metal  which  is  absorbed  from  the 
alimentary  canal  in  sufficient  quantity  to  produce  acute  poisoning 
other  than  corrosive. 

Chronic  poisoning  arises  because  excretion  is  slower  than 
ab.sorption. 


220    GENERAL  PROTOPLASM  POISONS  AND  MISCELLANEOUS 

Symptoms  of  Metallic  Poisoning. — G astro-intestinal. — Loss  of 
appetite,  pain  and  discomfort,  nausea,  vomiting,  purging,  hemor- 
rhages and  congestion.  Ulcers  may  occur  if  the  animal  lives  long 
enough.  Lead  and  some  others  may  induce  constipation  and 
griping,  but  they  may  also  elicit  purging. 

Kidney. — Irritation,  inflammation,  cirrhosis,  etc. 

Circulation. — ^Little  direct  action;  late  in  poisoning  some  action 
may  result  from  disorders  of  nutrition. 

Some  dilation  of  the  vessels  of  the  intestines  and  fall  of  blood- 
pressure.  In  the  case  of  lead  the  vessels  may  be  constricted  and 
pressure  high.  The  blood,  as  a  rule,  less  alkaline,  is  due  to  the 
increase  of  lactic  acid. 

Central  Nervous  System. — As  a  general  rule,  stimulation  of  some 
parts  and  depression  of  others.  Delirium,  hallucinations,  mania, 
stupor,  coma.  Convulsions  indicating  that  the  motor  areas,  basal 
ganglia  and  spinal  cord  are  affected.  The  different  types  of  convul- 
sions may  occur.  Lesions  of  the  brain  have  been  found.  Peripheral 
neuritis,  especially  with  lead  and  antimony.  This  neuritis  does  not 
differ  from  that  caused  by  alcohol  or  toxins. 

Metabolism. — Some  of  them  may  in  small  amounts  produce 
changes  similar  to  that  produced  by  phosphorus. 

Colloidal  Heavy  Metals. — Copper,  platinum,  silver,  etc.,  are  some- 
times used  in  medicine.  The  basis  for  their  use  is  the  action  of 
minute  amounts  of  copper  on  infusoria  and  other  unicellular  organisms. 

POTASSIUM  SALTS. 

Experiment  I. — Absorption  arid  Excretion. — (a)  Take  0.5  gram 
KI  in  a  capsule  and  test  the  saliva  every  ten  minutes  for  the  presence 
of  the  salt,  as  follows:  Place  the  saliva  in  a  test-tube  or  on  a  white 
tile  and  acidify  with  a  drop  of  nitric  acid,  then  add  a  few  drops  of 
1  per  cent,  starch  paste.  A  blue  color  indicates  the  presence  of 
iodin. 

(6)  Collect  the  urine  every  fifteen  minutes;  add  a  few  drops  of 
nitric  acid  and  a  few  drops  of  the  starch  paste. 

Experiment  11. — Action  of  Potassium  Salts  on  the  Heart  and  Vessels. 
— Prepare  a  turtle  heart  strip,  and  when  it  beats  rhythmically  in 
saline,  add  KCl  so  that  the  fluid  contains  0.01  per  cent  KCl,  0.02, 
0.04,  0.08  and  1  per  cent.  When  depression  is  marked,  replace  the 
solution  with  0.9  per  cent.  NaCl  solution. 

Experiment  III.^ — Action  of  Potassium  on  Reflex  Time. — Pith  a  frog 
and  study  the  reflex  time  by  Tiirck's  method.     Inject  0.5  c.c.  of 


AMMONIUM  221 

potassium  bromide  and  determine  the  change  in  reflex  time  after 
thirty  minutes. 

Experiment  IV. — Anesthetize  a  dog  and  take  blood-pressure  and 
respiration  tracings;  inject  1  per  cent,  of  KCl  slowly  until  the  heart 
is  markedly  depressed.  Then  inject  10  c.c.  of  1  per  cent.  CaCl2. 
Repeat  with  KCl. 

AMMONIUM. 

Experiment  I. — Give  a  dog  2  c.c.  of  3  per  cent,  morphin  sulphate 
hypodermically;  after  thirty  minutes  count  the  heart  and  respira- 
tion-rate. Now  inject  5  c.c.  of  2  per  cent,  ammonium  chloride  per 
kilo  and  note  the  changes  in  the  rate  of  the  heart  and  respiration. 
Anesthetize  the  animal;  prepare  for  blood-pressure  and  respiration 
tracings  and  for  injection  into  the  femoral  vein.  Slowly  inject  1 
per  cent,  ammonium  chloride  until  spasms  develop.  Notice  the 
character  of  these  and  compare  with  strychnin.  Finally,  give 
sufficient  strychnin  to  produce  tetanus. 

Experiment  II. — Inhalation  of  Ammonia. — Give  a  dog  2  c.c.  of 
3  per  cent,  morphin  h^T^odermically.  In  thirty  minutes  anesthetize 
with  ether.  Prepare  for  blood-pressure  and  respiratory  tracings. 
Isolate  the  vagi,  but  do  not  cut  When  the  animal  is  well  anesthe- 
tized let  him  inhale  a  10  per  cent,  solution  of  NH4OH.  What  is 
the  result?  Now  cut  the  vagi  and  continue  the  inhalation.  If 
spasms  do  not  develop  soon,  let  him  inhale  20  per  cent,  ammonia. 
Note  the  strength  of  the  solution.  If  allowed  to  inhale  a  weak 
solution  the  absorption  is  so  slow  that  spasms  do  not  develop  readily. 
Note  the  condition  of  the  lungs  at  the  end  of  the  experiment. 

Experiment  m. — (\)unt  the  pulse  and  respiration  of  a  rabbit. 
Hold  a  piece  of  cotton  with  ammonia  to  the  nose  of  the  animal 
or  blow  the  ammonia  vapor  into  the  nostrils.  Stoppage  of  the 
respiration  or  slowing  or  temporary  arrest  of  the  heart  follows. 
Trigeminal  vagus  reflex. 

Experiment  IV.— In  a  series  of  frogs  inject  into  the  abdominal 
lymph  sac: 

1.  0.2  c.c.  of  5  per  cent,  ammonium  chloride. 

2.  0.5  c.c.  of  5 

3.  l.Oc.c.  of  5 

4.  2.0  c.c.  of  5 

If  convulsions  develop,  note  the  type.  Pith  or  destroy  the  brain 
and  the  incdulla.  How  does  the  action  of  ammonia  dift'er  from 
strychnin '! 


222     GENERAL  PROTOPLASM  POISONS  AND   MISCELLANEOUS 

EXPERIMENTAL  GLYCOSUEIA. 

This  may  be  caused  by: 

1.  Lesions  of  the  nervous  system. 

2.  Asphyxia. 

3.  The  intravenous  injection  of  salts  and  drugs. 

4.  By  the  subcutaneous,  intravenous  or  intraperitoneal  adminis- 
tration of  epinephrin. 

5.  By  the  action  of  phloridzin. 

6.  Excessive  use  or  administration  of  sugar. 

The  mechanism  of  the  action  in  any  case  is  not  well  understood. 

Experiment  I. — Inject  1  or  2  c.c.  of  1  to  1000  epinephrin  subcu- 
taneously  into  a  rabbit.  In  two  hours  catheterize  and  test  the  urine 
for  sugar.  Too  large  a  dose  of  epinephrin  administered  may  kill 
the  animal. 

Experiment  II. — Give  a  rabbit  I  gram  of  phloridzin  dissolved  in 
5  c.c.  of  olive  oil  subcutaneously.  In  an  hour  catheterize  and  test 
the  urine  for  sugar. 

Experiment  III. — Draw  blood  from  the  femoral  or  jugular  vein  of 
a  dog  and  determine  the  amount  of  sugar  by  the  Benedict  method 
(page  242). 

Inject  into  the  abdominal  cavity  1  gram  of  phloridzin  dissolved 
in  about  7  c.c.  of  olive  oil.  In  one  or  two  hours  catheterize  and  test 
the  urine  for  sugar.  The  amount  may  also  be  determined.  Test 
the  sugar  concentration  of  the  blood  when  the  sugar  appears  in 
the  urine.  Give  a  rabbit  a  hypodermic  injection  of  3  c.c.  of  3  per 
cent,  morphin.  Collect  the  urine  after  two  hours  and  test  for  sugar. 
Is  there  any  change  in  the  type  of  respiration?  Is  Cheyne-Stokes 
type  manifest?    Morphin  causes  glycosuria  by  asphyxia. 

Experiment  IV. — Anesthetize  a  cat  and  inject  a  molecular  length 
of  the  solution  of  sodium  sulphate  slowly  into  the  femoral  or 
jugular  vein.  Cats  are  easily  killed  by  the  injection  of  sulphates 
if  it  is  made  too  rapidly.  Collect  the  urine  and  test  for  sugar 
frequently. 

Experiment  V. — Give  a  dog  or  cat  1  gram  of  potassium  cyanide 
by  mouth  in  50  c.c.  of  water.  When  death  occurs  collect  the  urine 
and  test  for  sugar  with  Fehling's  solution. 

BERNARD'S  METHOD  OF  PUNCTURING  THE  FLOOR  OF  THE 
FOURTH  VENTRICLE  (PIQURE). 

The  instrument  he  used  is  shown  in  the  figure  (Fig.  46).  The  end 
of  the  instrument  is  thin  and  chisel-like  and  fashioned  for  boring.   A 


BERXARD'S  METHOD  OF  PUXCTURING  THE  FLOOR     223 

very  thin  central  point,  about  1  mm.  long,  and  needle-like,  extends 
beyond  the  fluted  end.    This  sharp  point  punctures  the  floor  of  the 


Fig.  -10. — The  instrument  to  make  the  puncture  (piqilre). 


Fig.  47. — Occipital  bone  of  the  rabbit,  showing  landmarks  for  piqure  as  described 
by  Bernard.  On  the  head  of  the  rabbit  the  finger  is  run  along  the  central  line  until 
one  feels  the  tuberosity,  .4,  which  corresponds  to  the  .superior  occipital  process  B. 
Immediately  behind  this  process  (B)  the  needle  or  drill  is  worked  through  the  bone 
C,  C,  auditory  tubes. 


'PUNGURm  INSTRUMENT. 
•6EREBELLUM. 


AUDITORY 
TUBE^ 


MEDULLA 


ORim  OF  5EVENTH  NERVE. 

Fig.  48. — Outline  of  the  rabbit's  head,  to  .show  the  course  of  the  needle  in  piriurc. 

(After  Bernard.) 


fourth  vcntric-Ic  l)et\veen  acoustic  and  piicumogastric  nerves.  To 
accomplish  this  the  animal's  head  is  held  in  the  left  hand,  witlian 
assistant  holding  the  feet.  The  finger  of  the  right  hand  is  |)assed  over 


224    GENERAL  PROTOPLASM  POISONS  AND    MISCELLANEOUS 

the  skull  until  one  feels  the  tuberosity  figure  (Fig.  47).  Just  posterior 
to  this  tuberosity  the  instrument  is  inserted  between  the  spongy 
tissue  and  the  bone.  By  a  boring  pressing  movement  the  instru- 
ment is  forced  through  the  bone  into  the  cranial  cavity.  The 
instrument  is  then  directed  obliquely  to  the  middle  point  between 
the  angles  of  the  animal's  lower  jaw  (Fig.  48)  or  to  cross  a  line 
which  extends  from  one  ear  to  the  other.  During  this  operation  the 
least  movement  of  the  animal  may  cause  a  fatal  laceration  of  the 
respiratory  center.  The  attenuated  end  or  needle  of  the  instrument 
touches  the  bacilaire  when  the  instrument  is  withdrawn.  If  the 
operation  is  properly  done  the  animal  suffers  very  little  incon- 
venience. There  is  no  convulsion  or  great  disturbance  of  respira- 
tion. The  prolonged  point  of  the  instrument  touches  the  bone  and 
prevents  a  fatal  compression  of  the  nervous  tissue  by  the  thicker 
part  of  the  instrument.  The  animal  is  a  little  stunned  for  the 
moment,  but  rapidly  recovers.  In  one  or  two  hours  sugar  appears 
in  the  urine. 


TUBtRCLE  OF 
WtHZEL. 


<-    LOBE  OF 
CEREBELLUM. 


FLOOR  OF  FOURTH 
VEHTRICLL 

ORm  OF  VAGUS  tiERVE 

POINT  OF  CALAMUS 
•SCRIPTORIUS. 


Fig.  49. — -Showing  the  fourth  ventricle  of  a  rabbit.     (After  Bernard.) 


Practice  is  necessary  for  this  operation,  and  it  may  first  be  done 
on  the  dead  animal  and  a  postmortem  performed  to  locate  the  site 
of  the  puncture.  The  second  animal  may  be  anesthetized,  and  if 
a  dental  drill  or  other  suitable  instrument  is  at  hand  the  skull  may 
be  entered  by  that  means.  A  very  light  hat-pin  will  suffice  for  the 
puncture  needle. 

Diuretic  puncture:  A  similar  puncture  to  that  described,  but 
slightly  higher  in  the  calamus  results  in  a  polyuria  without  glyco- 
suria.   This  polyuria  may  last  as  long  as  forty-eight  hours. 


FERMENTS,  ENZYMES  AND  DIGESTANTS  225 

FERMENTS,  ENZYMES  AND  DIGESTANTS. 

All  focxl  is  digested  by  ferments.  Indigestion  is  one  of  the  most 
common  causes  of  sickness.  It  is  natural  to  think,  therefore,  that 
the  pharmacology  of  digestion  or  fermentation  would  be  highly 
important;  however,  such  is  not  the  case.  The  study  is  full  of 
interest,  but  of  little  value  so  far  as  the  practice  of  medicine  is  con- 
cerned. Digestants  are  prescribed  liberally,  but  are  almost  certainly 
useless,  and  the  practice  has  fallen  off  much  in  recent  years.  Besides 
being  prescribed  as  digestants,  enzymes  such  as  trypsin  and  papain 
have  been  injected  into  pathological  tissues  with  the  idea  of  digesting 
them,  and  so  acting  as  caustics.  The  most  important  enzymes  in 
pharmacology  may  be  classified  as  follows: 

1.  Coagulating — thrombin  and  rennet. 

2.  Amidases — ptyalin  and  amylopsin. 

3.  Pepsin. 

4.  Tr\'psin. 

5.  Erepsin. 

6.  Catalases   or   those   that   liberate   oxygen  from   hydrogen 

peroxide. 

The  general  properties  of  these  need  not  be  rehearsed.  We  know 
nothing  of  their  structure,  as  they  are  colloids  of  unknown  composi- 
tion, and  as  such  are  killed  by  heat,  antiseptics,  etc.  When  injected 
intra^•enously  they  produce  toxic  symptoms  resembling  albumoses 
and  peptones;  but  this  may  be  due  to  adhering  albuminoid  mate- 
rial. Powders  like  kaolin  or  charcoal  when  shaken  with  solutions  of 
ferments  absorb  the  ferment.  In  the  same  way,  and  perhaps  to  a 
greater  extent,  ferments  are  absorbed  by  the  material  upon  which 
they  act  probably  because  of  electrical  attraction.  (For  a  detailed 
account  of  enzymes,  see  Biochemical  Catalysts  in  Life  and  Industry, 
Effront  and  Prescott,  also  Oppenheimer,  Die  Fermente.) 

Experiment  I. — In  a  series  of  test-tubes  place  5  c.c.  of  milk,  5  c.c. 
of  reiniin  and  5  c.c.  of  the  following  solutions: 

1.  Water. 

2.  Physiological  saline. 

3.  Formaldehyde  1  to  KKK). 

4.  Mercuric  chhjride  1  to  lOOO. 

5.  Pancreatin,  0.1  per  cent. 

6.  Phenol,  1.1  percent.  • 

7.  AgN():i,  0.1  per  cent. 

8.  KOI  I,  0.1  i)er  cent. 
0.  IICI,  0.1  jRT  cent. 


226     GENERAL  PROTOPLASM  POISONS  AND  MISCELLANEOUS 

Experiment  II. — Repeat  Experiment  I,  using  5  c.c.  of  1  per  cent, 
starch,  5  c.c.  of  saliva,  diluted  one-half  and  filtered,  and  5  c.c.  of 
the  above  solutions. 

Experiment  III. — Repeat  Experiment  I,  using  5  c.c.  of  1  per  cent, 
trypsin,  5  grams  of  washed  fibrin  and  5  c.c.  of  the  solutions  in 
Experiment  I. 

Experiment  IV. — ^Run  about  10  c.c.  of  blood  from  an  artery  into 
3  c.c.  of  the  following  solutions: 

1.  Water. 

2.  Liquor  sodii  chloridi  physiologicus. 

3.  5  per  cent,  peptone. 

4.  Saturated  magnesium  sulphate. 

5.  1  per  cent,  potassium  oxalate. 

6.  1  per  cent,  hirudin. 

7.  0.1  per  cent.  KOH. 

8.  0.1  per  cent.  HCl. 

9.  1  per  cent,  sodium  citrate. 
10.  1  per  cent,  sodium  carbonate. 

Discuss  results  in  each  case. 


CHAPTER  XXIII. 

PHARMACOLOGY  OF  THE  BLOOD. 

Function. 
Volume. 

Relative  I'ulumes  of  Corpuscles  and  Serum. 
Viscosity. 

Clotting. — Calcium,  adrenalin,  gelatin,  hirudin,  peptone,  oxalates, 
fluorides,  etc. 
Alkalinity, 
Acidosis. 

Distribution  in  Tissues. 
Drugs  and  Conditions  Changing  J^olume  and  Distribution. 

Laking. 

Composition. 

Sugar,  content  of. 

Glycolysis. 

Detoxicating,  action  of.  '' 

Blood-pressure:  Muscle,  nerves,  heart. 

FUNCTIONS  OF  THE  BLOOD. 

The  Functions  of  the  blood  are: 

1.  To  carry  nutritive  and  energy-yielding  material  to  the  tissues. 

2.  To  carry  waste  products  from  the  tissues. 

3.  It  is  the  medium  of  transmission  of  the  internal  secretions. 

4.  It  aids  in  regulating  the  temperature  of  the  body. 

5.  It  carries  oxygen  from  the  linigs  to  the  tissues  and  carbon 
dioxide  from  the  tissues  to  the  lungs,  to  the  respiratory  center  and 
wherever  needed.     ' 

These  functions  relate  blood  closely  to  every  tissue  in  the  body, 
and  changes  in  the  blood  must  modify  the  function  of  each  tissue; 
but  the  physiology  or  pharmacology  of  the  blood  itself  may  be 
studied  without  reference  to  any  other  tissue. 

To  perf(;rm  its  functions  normally,  blood  has  certain  qualities  or 
properties  and  drugs  may  modify  tliese,  quantitatively  only: 

I.  Vohirne.—  'rhv  amount  of  l)]()od  in  the  vessels  is  normally 
one-thirteenth  to  oiic-fourteciith  of  the  body  weight,  and  serious 


228         OUTLINE  FOR  PHARMACOLOGY  OF  THE  BLOOD 

consequences  follow  any  marked  variation  in  the  total  volume  or 
its  distribution. 

2.  Distribution. — The  distribution  of  this  among  the  various 
organs  in  the  rabbit  is  given  by  Ranke  as  follows  ■} 

Per  cent. 

Spleen 0.23 

Brain  and  cord 1 .  24 

Kidneys 1.63 

Skin 2.10 

Intestines 6.30 

Bones 8.24 

Heart,  lungs,  large  vessels 22.76 

Resting  muscles 29.20 

Liver 29.30 

There  is  little  occasion  to  attempt  a  reduction  of  the  volume  of 
the  blood  by  drugs,  though  in  cases  of  plethora  it  might  be  bene- 
ficial. As  a  matter  of  fact,  however,  it  is  not  a  very  successful 
undertaking.  Diaphoresis,  diuresis,  catharsis  and  the  withholding 
of  fluids  from  the  food  or  drink  may  lessen  the  volume  somewhat, 
but  the  object  of  such  treatment  is  usually  to  remove  toxins  or  other 
poisonous  material  or  to  favor  the  absorption  of  pleural,  peritoneal 
exudates  or  edematous  fluid  rather  than  to  reduce  the  volume  of  the 
blood  primarily. 

VOLUME  OF  THE  BLOOD. 

The  volume  may  be  increased  by  excessive  drinking;  the  result, 
however,  is  very  temporary.  Anything  that  causes  a  dilation  of  the 
vessels,  as  the  nitrites,  may  cause  a  very  transient  increase.  Usually, 
however,  the  increase  in  volume  is  local,  because  drugs  that  dilate 
the  vessels  usually  do  so  locally  and  not  generally. 

Increasing  the  volume  of  the  blood  is  a  more  frequent  and  suc- 
cessful undertaking.  After  cases  of  severe  hemorrhage  a  trans- 
fusion of  blood  is  6ften  made.  Similarly,  after  operation  or  shock 
the  blood-pressure  may  be  raised  by  increasing  the  blood  volume 
either  by  transfusion  or  by  the  injection  of  saline.  In  cases  of 
chlorosis  or  anemias,  iron  and  other  drugs  may  increase  the  blood 
volume  by  increasing  or  building  up  red  corpuscles.  Hygienic 
and  dietetic  treatment  may  yield  similar  results. 


VISCOSITY. 

A  certain  viscosity  seems  necessary  for  blood  to  perform  its 
proper  function.    If  there  be  deficient  colloidal  matter  to  which  the 

1  Howell,  p.  458. 


VISCOSITY  229 

viscosity  is  due,  the  fluid  tends  to  leave  the  vessels  and  to  accumu- 
late in  the  tissues.  This  is  the  cause  of  the  relative  failure  of  saline 
injection  in  cases  of  low  blood-pressure  due  to  shock  or  hemorrhage. 
It  has  been  found  in  these  cases,  if  saline  alone  be  injected,  that 
the  rise  in  blood-pressure  may  be  relatively  short,  because  the  fluid 
leaves  the  vessels  either  by  way  of  the  kidney  or  into  the  tissues 
to  cause  an  edema.  For  this  reason  the  addition  of  gum  arabic  or 
some  other  colloid,  or  the  transfusion  of  blood,  has  been  advocated. 
Diminished  viscosity  also  permits  certain  crystalloids  like  sugar 
to  pass  through  the  kidneys  and  perhaps  also  into  the  tissues.  This 
can  easily  be  shown  by  comparing  the  rate  of  dialysis  in  whole 
blood  and  serum.  Sugar  will  dialyze  from  serum  much  more  readily 
than  from  the  whole  blood. 

Adrenalin  and  calcium  salts  increase  the  clotting  of  the  blood  and 
perhaps  also  its  viscosity,  while  oxalates,  potassium  iodide  and 
fluoride,  organic  substances,  such  as  peptone,  pepsin,  snake  venom 
or  hirudin,  lessen  viscosity. 

Anything  that  lessens  the  amount  of  protein  in  the  blood  or  the 
volume  of  the  corpuscles  may  lessen  viscosity. 

Normally,  the  protein  of  the  blood  is  about  8  per  cent.  The 
volume  of  the  corpuscles,  however,  is  about  one-half  the  total 
volume.  Consequently,  we  should  expect  the  blood  to  be  of  much 
greater  viscosity  than  water. 

The  proteins  are  hydrophyllic  colloids.  Changes  in  acidity  or 
alkalinity  markedly  modify  the  water-holding  capacity  of  the  pro- 
teins and  consequently  change  the  viscosity. 

This  viscid  character  is  the  most  striking  distinction  of  the 
organic  and  inorganic  colloids.  An  8  per  cent,  solution  of  blood  has 
4.4  to  5.5  times  the  viscosity  of  water.  The  viscosity  of  the  blood 
is  greater  than  serum,  although  the  serum  volume  for  volume  con- 
tains almost  twice  as  much  protein  as  the  blood,  GO  to  39. 

The  viscosity  bears  a  close  relation  to  the  number  of  corpuscles, 
as  shown  by  the  following  table  :^ 

Number  of  corpuscles  Viscosity  of  serum 

per  cubic  millimeter.  plus  corpuscles. 

0  1.9 

3.2  times  10«  3.3 

6.3  "      10"  4.9 
12.6      "      10"                                                          15.6 

Increase  in  temperature  reduces  the  viscosity,  since  at  37° 
it  is   10  per  cent,  less  than  at   17°.     An  increase  of  5°  in  fever 

•  Mathews:   Physiological  Chemistry,  p.  .'512. 


230         OUTLINE  FOB  PHARMACOLOGY  OF  THE  BLOOD 

may  reduce  the  viscosity  4  per  cent.  Increase  in  the  hydrogen  ion 
concentration  of  the  blood  increases  the  viscosity.  Since  CO2 
increases  the  hydrogen  ion  content,  venous  blood  has  a  greater 
viscosity  than  arterial.  Dyspnea  increases  it;  hunger,  salts,  diminish 
it,  while  a  meat  diet  increases  viscosity.  There  are  many  condi- 
tions in  the  practice  of  medicine  when  the  heart  requires  rest  and 
relief  from  overwork  and  the  viscosity  of  the  blood  is  important, 
since  the  greater  the  viscosity  the  more  work  is  placed  on  the  heart 
to  keep  it  circulating. 

CLOTTING  OF  THE  BLOOD. 

Clotting  is  another  mechanism  for  increasing  the  viscosity, 
but  the  phenomenon  is  so  striking  that  it  is  generally  considered 
by  itself.  However,  the  mechanism  may  be  an  extreme  case 
of  protein  swelling  due  to  absorption  of  water,  such  as  occurs  when 
an  acid  is  added  to  gelatin.  It  is  rendered  more  hydrophyllic, 
swells,  and  has  a  greater  viscosity. 

This  is  an  important  fundamental  property  of  the  blood,  since 
if  it  were  not  present,  everyone  would  be  a  hemophilic,  or  rather 
none  would  survive.  It  is  a  property  essential  to  life.  The  real 
nature  of  it  is  not  fully  understood  and  probably  will  not  be  until 
we  know  more  of  the  nature  of  matter. 

It  is  generally  accepted  that  the  fibrin  formed  during  the  clotting 
is  derived  from  fibrinogen.  This  substance  can  be  prepared  in 
solution  free  from  other  proteins. 

The  mechanism  of  the  clotting  has  been  presented  by  Howell  in 
his  Physiology.    He  prepares  fibrinogen  as  follows: 

Collect  horses'  or  cats'  blood  by  allowing  it  to  escape  from  the 
vessel  without  coming  in  contact  with  the  wounded  surface  or  tissue 
into  a  solution  of  sodium  oxalate  of  such  strength  that  the  final 
volume  contains  0.1  per  cent,  oxalate. 

Centrifuge  and  obtain  clear  plasma  and  add  an  equal  volume  of 
saturated  sodium  chloride.  This  precipitates  fibrinogen,  centrifuge 
and  remove  the  supernatant  liquid.  Wash  with  a  half-saturated 
solution  of  NaCl  and  then  dissolve  with  stirring  in  a  2  per  cent, 
solution  of  NaCl  and  filter.  This  is  precipitated  again  by  half- 
saturation  with  NaCl,  centrifugalized,  washed  and  the  process 
repeated  a  third  time,  and  the  washed  precipitate  dissolved  in  a 
1  per  cent,  solution  of  NaCl.  It  is  sometimes  necessary  to  add  a 
few  drops  of  a  0.5  per  cent,  solution  of  sodium  bicarbonate  to  get 
this  last  precipitate  into  solution. 


CLOTTING  OF  THE  BLOOD  231 

The  solution  so  prepared  will  not  clot  except  on  the  addition  of 
blood  serum  containing  the  so-called  fibrin  ferment  thrombin. 
If  instead  of  thrombin  Ca  salts  be  added,  and  some  sodium  bicar- 
bonate about  the  same  concentration  as  in  Ringer's  solution,  a  clot 
may  be  formed,  but  very  slowly. 

This,  Howell  thinks,  is  due  to  the  fibrinogen  containing  a  ti-ace 
of  thrombinogen,  the  antecedent  of  thrombin. 

Thrombin  may  be  prepared  as  follows:  Allow  blood  to  clot, 
remove  the  serum  and  precipitate  with  20  volumes  of  alcohol, 
let  stand  for  a  week  and  then  filter.  Dry  the  precipitate,  grind  it 
and  extract  it  with  water.  The  aqueous  solution  contains  thrombin 
in  addition  to  other  proteins.  A  solution  made  in  this  way  will 
cause  the  precipitation  of  fibrinogen.  That  thrombin  is  not  present 
in  normal  blood,  however,  is  shown  by  the  fact  that  blood  led 
directly  from  the  artery  into  alcohol  and  extracted  in  the  same 
manner  as  above  will  not  yield  a  clot. 

Calcium  is  necessary  for  normal  clotting.  This  was  shown  by 
Arthus  and  Pages  by  adding  sodium  oxalate  to  plasma,  so  that  the 
concentration  was  0.1  per  cent.  It  was  then  dialyzed  until  the  excess 
of  oxalate  was  removed.  Dialyzed  plasma  will  remain  unclotted 
indefinitely,  but  clots  immediately  if  a  little  calcium  be  added. 

The  role  of  calcium  in  clotting  is  in  the  conversion  of  prothrombin 
into  thrombin,  because  it  has  been  shown  by  Hammarsten  that 
dialyzed  oxalated  plasma  is  readily  clotted  if  some  thrombin  solu- 
tion free  from  calcium  be  added  to  it. 

The  process  of  clotting  may  be  represented  as  follows: 

Ca  +  thrombinogen  =  thrombin. 

Thrombin  +  fibrinogen  =  fibrin. 

Since  blood  that  comes  in  contact  with  tissues  clots  much  more 
quickly  than  blood  drawn  without  touching  tissue,  it  is  generally 
accepted  that  the  tissues  furnish  an  activator  or  kinase — thrombo- 
kinase  that  hastens  clotting.  To  illustrate  this  properly  the  following 
formula  is  used : 

Cellular  elements  =  thrombokinase. 

Thrombokinase  +  calcium  +  thrombinogen  =  thrombin. 

Thrombin  +  fibrinogen  =  fibrin. 

The  pharmacology  of  clotting  is  concerned  with  any  changes 
in  the  bkjod  or  its  environment  that  alter  the  rate  or  nature  of 
clotting. 

Means  of  Hastening  or  Retarding  Clotting.— Ik'forc;  nil  operations 
the  clotting  tiinc  is  or  should  be  dcterniiiicd.  Normally,  blood  clots 
in  from  three  to  ten  minutes.  If  for  any  reason  clotting  does  not 
occur,  or  is  long  delayed,  the  operation  may  l)e  contra-indicated. 


232         OUTLINE  FOR  PHARMACOLOGY  OF  THE  BLOOD 

Conditions  Delaying  or  Preventing  Clotting  are:  1.  Loiv  Tempera' 
tiire. — This  can  best  be  shown  with  blood  that  normally  is  slow  in 
coagulating.  The  blood  of  the  horse,  terrapin  or  birds  coagulates 
slowly.  If  horse's  blood  be  collected  in  narrow  vessels  surrounded 
by  ice  the  clotting  is  so  long  delayed  that  the  corpuscular  elements, 
being  of  greater  specific  gravity  than  the  plasma  will  sink  gradually 
to  the  bottom  and  the  clear  yellow  plasma  can  be  pipetted  off. 
Similarly,  with  the  blood  of  all  species,  clotting  is  delayed,  but  in 
most  cases  coagulation  even  on  cooling  will  be  too  rapid  for  the 
preparation  of  plasma. 

2.  Coagulation  is  delayed  hy  anything  that  precipitates  or  removes 
calcium  as  the  oxalates  or  citrates.  These  remove  the  calcium  in 
insoluble  form,  and  prevent  the  formation  of  the  ferment  necessary 
for  clotting. 

3.  Strong  solutions  of  MgSOi,  and  of  Na^SOi  prevent  clotting.  The 
explanation  of  this  is  not  well  understood,  but  it  is  believed  to  be 
due,  in  a  measure,  to  their  preventing  the  disintegration  of  the  cellu- 
lar elements,  thus  delaying  or  preventing  the  formation  of  thrombo- 
kinase.  It  is  known  that  tissue  products  accelerate  clotting  and  that 
blood  within  the  veins  does  not  readily  clot.  It  may  also  be  due  to 
the  precipitation  of  the  calcium  with  these  strong  sulphate  solutions. 
Similarly: 

4.  Sodium  Fluoride  prevents  clotting,  perhaps  by  precipitation  of 
the  calcium  as  fluorides.  It  may  also  lessen  ferment  action,  and 
this  would  be  an  additional  factor. 

5.  Certain  organic  substances,  like  pepsin,  trypsin,  peptone  and 
hirudin,  when  injected,  intravenously,  prevent  clotting.  The 
mechanism  of  the  action  here  is  not  understood,  but  it  may  be  that 
these  bodies  cause  an  increase  of  antithrombin.  Prevention  of 
clotting  is  of  use  only  in  experimental  work.  It  is  never  desired  in 
medicine. 

Agents  Hastening  Clotting. — Much  more  important  than  delaying 
clotting  is  the  hastening  of  it.  This  cannot  be  done  in  the  best 
way  until  we  understand  normal  clotting.  Since  calcium  is  neces- 
sary for  clotting,  one  of  the  first  methods  employed  to  hasten  clotting 
is  the  administration  of  calcium  salts.  The  value  of  these  is 
questionable. 

The  intravenous  injection  of  adrenalin  also  aids  clotting.  If  this 
be  given  too  quickly,  however,  there  is  danger  from  the  increased 
blood-pressure. 

Pressure  to  a  bleeding  surface  aids  coagulation,  and  the  presence 


THE  ALKALINITY  OF  THE  BLOOD  AND  ACIDOSIS      233 

of  gauze,  sponges,  or  clothes,  or  other  bodies  also  aids.  Pressure 
by  causing  the  liberation  of  thrombokinase  and  acting  as  a  foreign 
body  furnishes  a  nucleus  for  the  deposit  of  fibrin  crystals,  and  also 
aid  in  the  rupture  of  blood  platelets,  etc.,  and  in  this  way  hasten 
coagulation. 

THE  ALKALINITY  OF  THE  BLOOD  AND  ACIDOSIS. 

One  of  the  essentials  of  life  is  an  alkaline  reaction.  The  actual 
alkalinity,  while  near  neutrality,  is  yet  insured  against  this  actual 
neutrality  by  a  reserve  or  potential  alkalinity  that  is  available  in 
case  of  necessity. 

An  acid  reaction  is  due  to  an  excess  of  H  ions;  alkalinity  is  due 

to  free  OH  ions.     In  water  which  is  neutral  in  reaction,  the  H  and 

OH  ions  are  in  equal  numbers,  H  times  OH=10-i^     The  product 

of  H  and  OH  in  any  dilute  solution  is  always  equal  to  this  figure, 
consequently,  when  we  know  one  we  can  calculate  the  other.  An 
increase  of  H  ions  means  a  diminution  of  OH  ions  and  vice  versa. 

Hydrogen  Ion  Concentration.- — By  this  expression  we  mean  the 
concentration  of  dissociated  H,  in  terms  of  a  normal  solution. 
For  example,  if  one  gram  of  hydrogen  is  dissociated  in  10,000,000 
liters  of  water  the  concentration  is  10"^  normal. 

Method  of  Expressing  H  Ion  Concentration. — It  would  obviously 
be  cumbersome  to  express  a  dilution  of  one  molecule  of  dissociated 
H  in  10,000,000  liters  of  water  by  0.0000001  and  in  biological  work 
we  are  dealing  mainly  with  these  dilutions.  A  less  cumbersome 
method  of  notation  is  therefore  advisable.  Consequently,  the  above 
dilution  is  written  H  =  10-^  At  the  present  time  the  custom 
is  to  use  the  logarithm  only  and  to  avoid  the  negative  sign.  The 
reciprocal  7  is  used  so  that  10^  really  would  mean  10"^ 

In  order  to  save  space  and  to  express  the  concentration  expli- 
citly, Sorensen  has  suggested  a  plan  which  is  very  widely  adopted. 
He  expresses  the  potential  or  concentration  of  the  H  ions  as  PHi, 
PH2,  PH3,  etc.,  where 

PHi  =  /o  acid  or  H    =    10-' 

PH«  =TOfto'«oo    acid  or  H    =    lO"" 

PH?  =  Neutrally  or  H    =    10"' 

PHs  =    Tftooooo    alkali  or  H    =    lO's 

PHh  =  xff  alkali  or  H    =    10"" 

PHu  =     r  alkali  or  H    =    lO"'^ 


234         OUTLINE  FOR  PHARMACOLOGY  OF  THE  BLOOD 

This  system  is  brief,  but  confusing  until  studied.  Since  the 
numbers  refer  to  negative  logarithms  the  higher  the  number  the 

fewer  H  ions  in  a  given  volume,  while  the  OH  ions  increase.    This 

+ 
is  quite  comprehensible  when  we  remember  that  H  times  OH  is 
always  14  or  10~^*.  If  PH  is  14,  it  follows  that  OH  must  be  zero, 
and  if  PHi  is  y^  acid  P  OHimust  also  be  yq  alkali.  As  now  employed 
Sorensen's  figures  are  the  logarithms  of  the  dilution  in  terms  of 
normal  solution. 

PHi4  is  y  alkali,  and  when  H  is  PHi3  =  P0Hi  the  solution  is 
Yq  alkali. 

Potential  Alkalinity. — The  weakly  alkaline  condition  of  the  blood 
is  guaranteed  by  a  mixture  of  H2CO3,  NaHCOs  and  NaH2P04. 
These  are  all  very  weakly  dissociating  substances  and  may  be 
considered  in  the  blood  to  be  in  a  balanced  state: 


H2CO3  ,^       J    NaH2P04 

=  K  and  —  ^  ^^  ^^      =  K2 


NaHCOs  N2H  PO4 

When  K  and  K2  are  constants  and  the  sum  of  these  constants  in 
terms  of  H  ions  is  about  PH,  7.1  to  7.8  and  may  be  briefly  repre- 
sented as: 

H2CO3 


NaHCOs 


Ki 


If  acid  be  added  to  this  directly  or  indirectly,  as  in  cases  of 
acidosis,  it  liberates  H2CO3.  This  will  either  break  into  CO2  and 
H2O  and  K,  kept  constant,  or  it  will  tend  to  act  with  Na2C03  if 
such  be  present  and  restore  the  constant  in  that  way.  If  enough 
acid  be  added  or  developed  the  whole  alkali  reserve  may  be 
exhausted.  The  phosphates  are  balanced  in  the  same  way. 
According  to  Michaelis  and  Garmendia  the  ratio  of 

NaH2P04         1        ,      , 

„^^     =  -.r—^  molecules. 

Na2HP04        5.1 

Since  the  normal  blood  always  contains  CO2,  NaHC03  and  Na2 
HPO4  in  this  balanced  state  the  H  ion  concentration  at  any  one 
time  cannot  be  determined  by  titration,  because  as  fast  as  the 
actual  alkalinity  is  removed  the  potential  alkalinity  is  converted 
into  actual.  Consequently,  the  titration  alkalinity  is  the  sum  of 
actual  and  potential. 


SPECIFIC  GRAVITY  OF  BLOOD  235 

This  difference  between  the  actual  and  total  alkalinity  of  the 
blood  is  known  as  the  "buffer"  value  and  NaHCOa  and  Xa2  HPO4 
are  the  buffers,  XaHCOs  especially.  The  value  of  this  buffer  is 
illustrated  by  comparing  the  effect  of  acid  added  to  a  liter  of  water 
and  to  a  liter  of  XaHCOs.  The  reaction  of  a  solution  of  pure 
X'aHCOs  is  very  weakly  alkaline.  Water  is  neutral.  A  drop  of 
acid  added  to  a  liter  of  water  will  definitely  acidify  it.  When 
added  to  a  solution  of  X'aHCOs,  however,  it  will  not  change  the 
actual  alkalinity  and  will  not  exceed  the  acidity  of  CO2  until  all  of 
the  X'aHCOs  has  been  decomposed.  The  amount  of  acid  required 
to  do  this  will  depend  on  the  amount  of  the  X'aHCOs  in  solution. 
In  other  words,  on  the  buffer  value  of  the  solution.  The  carbonates 
are  the  chief  biological  buffers. 

Acidosis.  The  actual  significance  of  this  term  varies  in  many 
minds.  As  generally  accepted,  a  state  of  acidosis  exists  w^hen  large 
amounts  of  acetone,  aceto-acetic  acid,  and  in  the  more  severe  cases, 
^-oxybutyric  acid,  are  excreted  in  the  urine.  This  occurs  frequently 
in  diabetes.  The  actual  alkalinity  of  the  blood  may  not  be  changed 
for  a  long  time,  but  these  bodies  as  they  are  excreted  combine 
with  and  exhaust  the  reserve  alkalinity  or  buffer  alkalinity. 

Normal  adults  excrete  3  to  15  mg.  of  combined  acetone  and  aceto- 
acetic  acid  per  day.  Over  20  mg.  is  considered  pathological.  The 
amount  may  be  increased  by  fasting,  and  by  and  by  an  exclusively 
carbohydrate  diet,  diabetes,  intoxications  of  pregnancy  and  other 
diseases  may  cause  an  abnormal  amount  to  develop. 

SPECIFIC  GRAVITY  OF  BLOOD. 

The  specific  gravity  of  the  blood  has  so  far  been  no  aid  in  diagnosis. 
Normally  it  varies  between  1.045  to  1.075.  The  simplest  method 
of  determining  the  specific  gravity  is  that  of  Hammerschlag,  which 
consists  of  mixing  CIICls,  specific  gravity  1.520,  and  benzol,  specific 
gravity  0.090,  until  the  mixture  has  the  specific  gravity  of  about 
1.055  as  <letermined  by  a  spindle.  A  drop  of  the  blood  is  then 
dropijed  in,  and  if  it  sinks  CHCI3  is  added,  and  if  it  rises  to  the  top, 
benzene  is  added  until  the  gravity  of  the  blood  is  obtained,  when 
the  blood  will  float  without  any  marked  tendency  to  rise  or  fall. 
The  six'cific  gravity  of  the  mixture  is  then  determined.  The  action 
of  drugs  on  the  specific  gravity  is  very  slight. 

Laking  or  Hemolysis.— Hemolysis,  or  the  discharge  of  hemoglobin 
from  llir  <<jipiiscle,  is  important  in  pharmacology,  because  by  a 
knowledge  of  its  causative  agents  one  may  avoid  serious  accidents, 


236 


OUTLINE  FOR  PHARMACOLOGY  OF  THE  BLOOD 


and  because  many  drugs  and  diseases  may  cause  laking  and  hemo- 
globinuria.    The  agents  that  may  cause  laking  are: 

1.  Water  or  hypotonic  solutions  intravenously. 

2.  Ether,  chloroform  or  alcohol. 

3.  Soaps  and  fatty  acids. 

4.  Blood  from  a  different  species,  and  in  some  cases  of  transfusion 
hemolysis. 

5.  Bile  and  bile  salts. 

6.  Certain  drugs,  as  KCIO3,  saponins,  gallic  acid,  sapotoxins, 
alkalies  and  solanin. 

7.  Toxins  of  bacteria  and  snake  venom. 

8.  Exposure  to  cold  may  cause  some  laking,  especially  alternate 
freezing  and  thawing. 

The  direct  harmful  effect  is  disturbance  of  oxidation,  metabolism, 
injury  to  kidneys,  heart  or  central  nervous  system  either  from 
anemia  or  the  products  liberated  by  the  destruction^of  hemoglobin. 


Red     Orange  Yellow 


Green 


Cyan-blue 


A      a      B     C 


D 


Eb  F 

iO  50  60  70  80  90  100  110 

1 1  il|iiiliiil  null  1 1 1 1 1 1 1 1  1 1 II  liii  I  Inn  liiiiliiiijii  iiliiiiliii  ilii  iilii  M 


Fig.  50. — Spectrum  of  hematin  in  alkaline  solution,     (v.  Jaksch) 
Red     Orange  Yellov)  Green  Otian-blue 


A      a      B      C  D  Eb  F 

40  50  60  70  80  90  100  11.0 

I  I  I  I  I  I  I  I  1 1  I  II  1 1 1  I  I  I  I  I  I  I  I  I  Ijll  I.I  l.l.l.l.ll  J.IJ..I..I.I  I  1 1  I  1 1  I  I  I  I  I  I  I  I  I  I  I  I  I  I  I  I  I  I  I  I  I  I  I  I  I  M  I 


Fig.  51. — Spectrum  of  reduced  hemoglobin,     (v.  Jaksch.) 

Red  Orange  Yellow  Green  Oyan-bhie 

A       a      B      C  D  Eb  F 

40  50  60  70  80  90  100  ho 

1 1 1 1 1 1 1 1  I.I  n  I  1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1,1 1 1 1 1 1 1 1 1 1  i.i.i  1 1 II 1 1 1 1 1 1 1 1 1 1 1 1 1 II 1 1 1 1  M 1 1 1 II 


Fig.  52. — Spectrum  of  reduced  hematin.     (v.  Jaksch.) 


Nature,  Amount,  and  Changes  in  the  Hemoglobin. — The  hemoglobin 
is  exceedingly  important  in  pharmacology  because  it  is  the  direct 


SPECIFIC  GRAVITY  OF  BLOOD  237 

oxygen  carrier  of  the  body  and  because  it  forms  compounds  very 
readily  with  many  gases.  Its  amount  and  functions  are  also  varied 
and  modified  in  many  diseases. 

Hemoglobin  is  a  conjugated  protein.  It  may  be  broken  up  by 
heat,  acid,  or  by  alkalies  into  a  protein,  globin,  and  a  pigment, 
hematin.  The  hematin  is  about  5  per  cent,  of  the  whole  molecule. 
Hemoglobin  is  therefore  a  compound  of  a  protein  and  hematin.  The 
composition  of  the  molecule  varies  in  different  animals.  Dogs'  hemo- 
globin, according  to  Jaquet,  is  about  C758Hi203Ni95S3FeO5.  Globin 
is  levorotary  while  hemoglobin  is  dextrorotary.  In  man  the  amount 
of  hemoglobin  is  about  14  percent,  of  the  blood  weight.  The 
amount  varies  under  different  conditions  and  the  determination  of 
the  amount  of  hemoglobin  is  a  routine  clinical  procedure.  There 
are  numerous  instruments  devised  for  the  purpose. 

Experiment  I. — Coagulation. — Anything  that  precipitates  the  cal- 
cium of  the  blood  will  delay  clotting.  Arrange  a  series  of  test-tubes, 
properly  labelled.  Collect  for  control  10  c.c.  of  blood  and  note  the 
clotting  time. 

(a)  Add  1  c.c.  of  XaCl  solution  and  save  this  also  for  control. 
Note  clotting  time  in  every  case. 

(6)  Add  1  c.c.  of  K  Fl.  solution. 

(c)  Add  1  c.c.  of  sodium  citrate  solution. 

(f/)  Add  1  c.c.  of  an  oxalate  solution. 

{e)  Add  1  c.c.  of  magnesium  sulphate  solution. 

(/)  Add  1  c.c.  of  peptone  solution. 

iq)  Add  1  c.c.  of  1  to  1000  adrenalin. 
Experiment  II. — Having  determined  the  clotting  time  of  the  blood, 
inject  se\eral  times  0.5  c.c.  of  roVo  epinephrin  solution,  and  after 
ten  minutes  again  determine  the  clotting  time.  After  this  has 
changed  inject  slowly  into  the  vein  5  grams  of  peptone  in  solution. 
After  fifteen  minutes  again  determine  the  clotting  time.  Note  the 
dift'erence  in  the  efi'ect  of  peptone  when  added  to  shed  blood  and 
when  injected  into  the  circulation. 

Experiment  HI. —  Viscosity. — KI  increases  the  fluidity  of  the  blood 
and  thoreff)re  lessens  the  viscosity.  CO2  increases  the  viscosity. 
These  are  perhaps  not  sufl^ciently  appreciated.  When  the  heart 
is  overworked  any  decrease  in  the  CO2  will  lessen  the  work  by 
lessening  the  viscosity.     KI  may  have  the  same  effect. 

Arrange  a  three-way  canmjla  with  a  very  small  outlet  so  that  the 
blood  drops  from  it  sufficiently  slow  to  be  counted.  Insert  in  a 
vein  and  count  fon  several  times.  If  clotting  takes  place  wash  out. 
When  an  average  of  the  drops  per  minute  has  been  found,  asphyxiate 


238         OUTLINE  FOR  PHARMACOLOGY  OF  THE  BLOOD 

the  animal  and  again  determine.  Allow  to  return  to  the  normal  and 
administer  1  or  2  grams  of  KI  intravenously  and  again  determine 
rate  of  flow.  This  will  give  an  idea  how  the  viscosity  may  be  deter- 
mined. There  are  many  sources  of  errors.  (See  Dunstan  and  Thole^ 
for  the  methods  of  determining  the  viscosity  of  colloids.) 

Alkalinity  and  Acidity  Changes  of  the  Blood. — Study  the  titratable 
and  actual  acidity  of  the  blood  and  the  meaning  of  each.  Assign  a 
review  of  Fischer's  theory  of  edema  and  its  importance  in  this 
respect.    Also  some  of  the  criticisms  of  the  theory. 

Experiment  IV. — Hemolysis  or  Laking. — Put  a  little  fresh  blood  in 
each  of  three  test-tubes.  Dilute  with  one,  two  and  three  volumes  of 
water.  Hold  over  a  printed  page  immediately  and  note  the  opacity. 
In  a  few  minutes  laking  will  occur  and  the  print  can  be  read 
through  the  liquid.  Laking  will  also  occur  if  bile  salts,  chloroform, 
dilute  acetic  acid,  in  0.9  per  cent.  NaCl,  ether,  saponin,  etc.,  are 
used.    Foreign  sera  and  toxins  also  cause  laking. 

Experiment  V. — Osmotic  Resistance  of  the  Corpuscle. — Fragility  of  the 
Corpuscle. — This  shows  why  water  cannot  be  injected  into  the  circu- 
lation without  injury  or  death  of  the  animal.  Arrange  a  series  of  ten 
test-tubes.  In  the  first  put  6  c.c.  of  1  per  cent.  NaCl,  in  the  next  5.8 
c.c,  in  the  third  5.6  c.c.  and  so  on,  each  differing  from  the  preceding 
by  0.2  c.c.  Now  add  sufficient  water  to  each  to  make  the  volume  in 
each  10  c.c.  This  is  done  by  adding  4  c.c.  to  the  first,  4.2  c.c.  to 
the  second  and  so  on.  Both  salt  solution  and  water  should  be  meas- 
ured from  accurate  burettes.  Put  into  each  tube  1  c.c.  of  fresh 
blood,  shake  moderately  until  mixed  and  allow  it  to  stand  from  ten 
to  thirty  minutes.  Observe  the  color  of  the  clear  liquid  in  the  tubes 
above  the  sediment.  Determine  in  which  tube  the  first  tinge  of 
hemoglobin  appears.  This  method  is  used  clinically  to  determine 
the  fragility  of  the  corpuscle. 

Crenation. — ^This  is  the  opposite  of  laking.  Add  5  per  cent,  of 
NaCl  to  the  blood  and  examine  under  the  microscope. 

Experiment  VI. — Changes  in  the  Oxygen  Carrying  Power  of  the  Blood ; 
Toxicology. — Examine  a  dilute  solution  of  normal  blood  with  the 
spectroscope  and  locate  absorption  bands. 

Carbon  Monoxide  Hemoglobin. — Pass  coal  gas  or  CO  through  blood 
for  a  considerable  time  and  again  examine. 

Methemaglobin." — ^Add  a  few  drops  of  a  strong  solution  of  potas- 
sium ferricyanide  to  blood  in  a  test-tube  and  heat  gently.  The 
color  changes  to  a  chocolate  tint.     A  distinct  band  is  seen  on  the 

1  The  Viscosity  of  Liquids. 


SPECIFIC  GRAVITY  OF  BLOOD 


239 


red  side  of  the  D  line.  (See  Beddard,  Practical  Physiology.)  On 
addition  of  ammonium  sulphide  this  band  disappears.  The  oxy- 
hemoglobin bands  are  seen  for  a  moment  and  then  give  place  to  the 
band  of  reduced  hemoglobin  (</.  v.). 


Red  Orange  Yellow 


Green 


Cyan-blue 


A       a      B      C 


I  IH|llll.lllllllllllllll  I 


Eh  F 

80  90  100  110 

l1|Mlllllllllllllll  llllllll  I  I  I 


Fig.  5.3. — Spectrum  of  oxyhemoglobin,      (v.  Jaksch.) ' 
Red  Orange        '  Telloio  Green  Cyan-bhte 


A     a      B      C  D 

10  50  60  70 


Eb 


F 

90  100 


HMlllllllIM 


lllllllllll  III 


Fig.  54. — ^Spectrum  of  carbon  monoxide  hemoglobin,     (v.  Jaksch.) 


Red  Orange  Yellow 


Green 


Cyun-hlue 


Eb 


A      a      B      C  D 

40  50  60  70  80  90  100  110 

I  I  I  I  I  I  I  I  I  I  I  I  I    I  I  I  I     I  I  I  I  I  I  I  I  I  I  I  I  M  I  I  I  I  I  I  I  I  I  !  I  I  I  M  I  I  I  I  I  I  1...1..|...I,.1.I,1J.„M  I  I  I  I  I  I  I  I  I  I  I  I  I  I 


Fig.  55. — Spectrum  of  methemoglobin  in  acid  and  neutral  solutions.       (v.  Jaksch.) 

Cyanhemoglobin. — The  blood  after  poisoning  with  cyanides  is  of  a 
bright  red  color — cyanhemoglobin?  It  is  easily  formed  by  adding 
IK'X  to  an  alkalinesolution  of  hematin  or  to  a  solution  of  methemo^ 
globin.  It  has  an  absorption  spectrum  very  similar  to  reduced 
hemoglobin.  Cyanhemoglobin  is  a  combination  of  methemoglobin 
with  cyanide.  A  very  delicate  test  for  cyanide  is:  Form  methemo- 
globin b\-  adding  a  little  amyl  nitrite  or  KCIO3  to  blood.  Place  a 
little  of  this  on  a  filter  paper.  If  a  trace  of  cyanide  be  added  to  one 
point  and  allowed  to  dry  the  paper  at  this  point  instead  of  being 
chocolate  brown  will  be  bright  red. 

Hematoporphyrin.— ^ihis  is  present  in  small  amounts  in  normal 
urine,  it  has  a  different  absorption  band  in  acid  and  alkaline 
solutions.  It  may  occur  especially  after  the  use  of  suljjhones.  In 
•such  ca.ses  the  urine  is  dark  red.  It  is  perhaps  isomeric  with  bilirubin 
and  gives  a  i)lay  of  colors  when  treated  with  finning  nitric  acid. 


240 


OUTLINE  FOR  PHARMACOLOGY  OF  THE  BLOOD 


Permeability  of  the  Red  Corpuscle. ^ — Ether,  esters,  aldehyde,  and 
acetone  divide  in  the  blood  so  that  the  corpuscle  contains  more  than 
the  serum.  Monatomic  alcohols  divide  equally  between  serum  and 
corpuscle,  diatomic  alcohol-glycol  about  equally.  Triatomic  and 
tetratomic  alcohols  penetrate  the  corpuscle  less  readily  while  there 
is  little  sugar  in  the  corpuscles.  Pentatomic  and  hexatomic  pass  in 
with  great  difficulty. 


Red  Orange 


Green 


Oyan-blue 


Fig.  56. — Spectrum  of  hematoporphyrin  in  alkaline  solution. 


The  Presence  of  Drugs  in  the  Blood. — It  is  perhaps  safe  to  say 
that  only  those  drugs  that  act  directly  on  the  blood — like  CO2, 
O2,  etc. — remain  for  any  length  of  time  in  the  blood.  Strychnin, 
for  example,  soon  leaves  the  blood  and  is  found  mainly  in  the 
nervous  system;  formaldehyde  if  introduced  into  the  blood  soon 
disappears  by  oxidation  or  otherwise. 

Drugs  which  are  not  decomposed  in  the  body  wander  in  and 
out  of  the  blood  in  absorption  and  excretion;  but  only  a  small 
concentration  is  found  in  the  blood  at  any  one  time.  In  many 
cases  this  small  amount  is  hard  to  detect. 

Experiment  I. — Anesthetize  a  dog  with  ether.  Record  respira- 
tion and  blood-pressure.  Insert  a  cannula  into  the  femoral  vein 
for  injection  of  solutions  and  a  cannula  into  the  carotid  artery 
to  take  the  blood  samples  for  analysis.  Inject  10  c.c.  formalde- 
hyde (about  6  per  cent.)  slowly  into  the  vein.  When  the  blood- 
pressure  is  at  the  lowest  point  withdraw  25  c.c.  of  blood,  acidify 
with  phosphoric  acid  and  distil  with  steam.  Test  the  first  20  c.c. 
of  the  distillate  for  formaldehyde  as  follows: 

Hehner's  Test. — Mix  5  c.c.  of  the  distillate  with  5  c.c.  of  milk 
(skim  milk);  add  an  equal  volume  of  concentrated  sulphuric  acid, 
containing  a  mere  trace  of  iron  (about  1  c.c.  of  1  per  cent. 
FcoCle  per  liter);  add  the  sulphuric  acid  carefully  so  that  it  does 
not  mix  with  the  milk  but  forms  a  layer  under  the  solution  to 
be  tested.  At  the  junction  of  the  liquids  a  violet  or  blue  color 
will  appear  if  the  milk  solution  contains  more  than  1  to  10,000 
formaldehyde. 


SPECIFIC  GRAVITY  OF  BLOOD  241 

Rimini's  Test  as  Modified  by  Schryver. — To  10  c.c.  of  the  distillate 
to  be  tested  add  2  c.c.  of  a  freshly  prepared  filtered  15  per  cent, 
solution  of  phenylhydrazin  hydrochloride.  Then  1  c.c.  of  freshly 
prepared  5  per  cent,  sodium  ferricyanide  and  5  c.c.  of  hydrochloric 
acid.  A  brilliant  magenta  color  is  produced.  The  test  is  sensitive 
up  to  1  part  of  formaldehyde  in  100,000. 

In  ten  minutes  again,  after  taking  the  first  sample  of  blood,  take 
25  c.c.  of  blood  and  again  test  for  the  presence  of  formaldehyde. 
If  it  is  still  present  repeat  again  in  fifteen  minutes. 

C'ollect  urine  at  the  end  of  the  experiment  and  test  either  directly 
or  after  the  distillation  as  in  case  of  the  blood. 

Experiment  II. — In  a  second  animal,  or  the  animal  used  for  for- 
maldehyde after  the  blood  no  longer  shows  the  presence  of  the  drug, 
inject  2  grams  of  hexamethylamin  in  50  c.c.  of  normal  saline  solu- 
tion. Test  the  blood  immediately  after  the  injection  and  every 
fifteen  minutes  thereafter  for  four  times  or  until  the  blood  shows 
no  formalin  test.  At  the  conclusion  of  the  experiment  test  the  urine 
for  formaldehyde. 

Experiment  in. — Give  a  dog  1  gram  of  sodium  salicylate  by  mouth 
in  solution  or  in  a  capsule  (preferably  in  solution).  Every  thirty 
minutes  withdraw  20  c.c.  of  blood  and  test  for  salicylates  as  follows : 
Dilute  with  50  c.c.  of  water,  acidify  with  dilute  acetic  acid  and  add 
10  grams  of  sodium  sulphate,  then  boil  and  filter.  To  5  c.c.  of  the 
filtrate  add  a  drop  of  ferric  chloride;  a  bluish  purple  color  indicates 
salicylic  acid.  Since  the  sodium  salicylate  in  the  blood  is  decom- 
posed on  acidifying  into  salicylic  acid  which  is  insoluble,  and  may 
be  removed  by  the  clot  on  filtering,  this  rough  test  may  not  show 
the  presence  of  salicylate  even  when  it  is  present  in  the  blood. 

A  direct  shaking  of  the  blood  with  ether  or  chloroform  is  not 
good  because  of  laking  and  solution  of  hemoglobin  in  the  solvent. 
Jji  such  cases  the  following  method  is  recommended:  Take  25  c.c. 
of  blood  and  dilute  to  100  c.c.  with  water.  Place  in  a  short-necked 
flask,  one  and  a  quarter  inches  in  diameter,  acidify  with  phosphoric 
acid  and  distil  with  steam.  The  distillation  of  the  salicylic  acid 
is  facilitated  by  submerging  the  flask  in  an  oil  bath  at  a  temperature 
of  from  120°  to  130°  C,  and  leading  a  current  of  steam  through  it, 
fjr  }>y  adding  20  grams  of  sodium  chh^ride  to  the  blood  solution  to 
raise  tli(;  boiliiig-j>oint.  J)o  not  char  the  blood  by  direct  heat.  Test 
the  distillate  direct  with  ferric  chloride  or  shake  the  distillate  with 
ether;  exajif^rate  the  ether  and  test  the  residue. 


16 


242         OUTLINE  FOR  PHARMACOLOGY  OF  THE  BLOOD 

CARBON  DIOXIDE. 

Experiment  I. — Anesthetize  a  dog  with  ether  and  prepare  for 
blood-pressure  and  respiratory  tracings.  Administer  CO2  from  a 
nitrous  oxide  apparatus.  Study  especially  the  action  on  the  blood- 
pressure.     Alternate  with  O2. 

Experiment  II. — Remove  the  mask  and  allow  the  animal  to  return 
to  normal.  Now  shut  off  the  trachea  with  a  clamp  and  take  a 
tracing  until  the  animal  shows  signs  of  impending  death;  then 
remove  the  clamp  and  resuscitate. 

Experiment  HI. — Give  curara  until  the  respiratory  muscles  are 
paralyzed.  Insert  a  tracheal  catheter  for  intratracheal  insufflation. 
Alternate  with  oxygen  and  carbon  dioxide  and  observe  the  effect  on 
the  heart. 

Experiment  IV. — Solid  carbonic  acid  (carbonic  acid  snow)  has  been 
used  as  an  irritant  in  chronic  inflammatory  conditions  also  as  a  local 
anesthetic,  due  to  its  freezing  powers.  It  is  also  used  for  the 
preparation  of  histological  sections. 

LEWIS-BENEDICT  METHOD  OF  DETERMINING  BLOOD  SUGAR. 

Dissolve  36  grams  of  picric  acid  in  50  c.c.  of  1  per  cent.  NaOH. 
Cool  and  dilute  to  1000  c.c.  Take  2  c.c.  of  blood  and  wash  out  into 
a  test-tube  with  4  c.c.  water  to  lake.  When  laking  is  complete  make 
up  to  25  c.c.  with  the  picrate  solution.  Shake  and  filter.  Measure 
8  c.c.  into  a  tube  graduated  at  12.5  c.c.  and  25  c.c.  Add  1  c.c.  of 
20  per  cent.  Na2C03  and  heat  in  a  water-bath  for  fifteen  minutes. 
Compare  the  color  of  this  solution  by  means  of  a  colorimeter  with 
that  of  a  0.1  per  cent,  solution  of  dextrose  in  picrate  solution  which 
has  been  treated  in  exactly  the  same  way  as  the  blood.  It  makes 
little  difference  what  volume  of  blood  is  taken  provided  the  same 
volume  of  the  standard  solution  is  taken.  The  volumes  given  in 
the  original  method  are  for  convenience  in  calculation  where  a 
permanent  standard  is  used.  I  believe  the  better  method  is  to 
make  the  standard  new  with  each  determination.^ 

PHLORIDZIN. 

Experiment  I. — Dissolve  0.25  gram  of  phloridzin  in  4  c.c.  of  olive 
oil  and  inject  subcutaneously  into  a  rabbit.  Collect  the  urine  with 
a  catheter  every  thirty  minutes  and  test  for  sugar. 

1  Jour.  Biol.  Chem.,  1915,  xx,  61;  ibid.,  1919,  xxxvii,  503. 


SAPONINS  243 

Experiment  II. — Give  a  rabbit  2  c.c.  of  epinephrin,  1  to  1000  hypo- 
dermically.    Collect  the  urine  and  test  as  in  Experiment  I. 

Experiment  III. — Take  a  sample  of  blood  from  a  dog  and  deter- 
mine the  amount  of  sugar  by  the  Benedict  method.  Dissolve  1 
gram  of  phloridzin  in  7  or  8  c.c.  of  olive  oil  and  inject  subcuta- 
neously  or  intraperitoneally.  Collect  the  urine  every  two  hours 
and  test  for  sugar.  When  sugar  appears,  determine  the  amount 
and  also  the  amount  in  the  blood  at  the  same  time. 

Experiment  IV. — Determine  the  blood-sugar  in  a  dog's  blood. 
Give  it  a  h^1^odermic  of  2  c.c.  of  epinephrin  every  fifteen  minutes 
for  five  times.  Collect  the  urine  at  the  end  of  two  hours.  Determine 
the  amount  of  sugar  in  the  blood  and  compare  with  the  phloridzin 
animal. 

SAPONINS. 

From  a  chemical  standpoint  most  saponins  are  non-nitrogenous 
glucosides,  but  because  of  some  striking  ph^^sical  actions  in  which 
they  resemble  soap  they  are  called  saponins.  They  foam  when 
shaken  in  water  and  emulsify  fats.  They  are  not  absorbed  from  the 
intact  alimentary  canal,  but  have  a  local  irritating  action.  In  small 
doses  they  are  expectorants.  Quillija,  senega  root  and  sarsaparilla 
owe  their  action  to  saponins.  They  are  little  used  for  this  purpose 
and  have  a  very  limited  use  in  medicine.  If  a  solution  of  saponin 
is  added  to  blood  or  injected  into  the  circulation  it  causes  a  laking 
of  the  red  corpuscles  with  free  hemoglobin  in  the  serum  and  urine. 
The  laking  is  due  to  changes  in  the  corpuscular  envelope.  The  most 
toxic  saponins  are  called  sapotoxins. 

Experiment  I. — Shake  a  few  drops  of  tincture  of  soap  bark  with  a 
little  water.  Xote  results.  Add  about  2  c.c.  tincture  of  soap  bark 
to  about  1  inch  of  cott(mseed  oil  in  a  test-tube  and  shake.  Result? 
What  is  emulsification? 

Experiment  II. — Shake  a  solution  of  saponin  in  water.  Study  the 
relation  fjf  sa])onin  to  surface  tension  by  placing  a  little  sulphur 
in  water  and  comparing  the  effect  with  sulphur  dusted  on  a  1  per 
cent,  saponin  solution.  How  would  you  detect  saponin  in  plant 
extracts? 

Experiment  III. — Laking  of  blood  by  saponin. 

(a)  I'o  .')  c.c.  of  blood  add  0.5  c.c.  of  8  per  cent,  saponin  solution 
in  0.9  i)er  cent.  Xa(^l. 

(h)  As  a  control  use  0.5  c.c.  of  0.9  per  cent.  XaCl  solution. 
Keep  the  mixtures  at  40°  C.  Laking  soon  occurs  in  the  saponin 
solution. 


244         OUTLINE  FOR  PHARMACOLOGY  OF  THE  BLOOD 

Experiment  IV. — Cholesterin  neutralizes  the  action  of  saponin. 
Prepare  test-tubes  as  follows : 

1.  Five  c.c.  of  0.9  per  cent.  NaCl. 

2.  Five  c.c.  of  0.9  per  cent.  NaCl,  containing  0.5  c.c.  of  3  per  cent, 
saponin. 

3.  Same  as  2,  but  in  addition  add  0.2  of  1  per  cent,  solution  of 
cholesterin  in  ether. 

4.  Five  c.c.  of  blood  plus  0.2  c.c,  cholesterin  in  ether. 

5.  Five  c.c.  of  distilled  water. 

To  each  tube  add  0.25  c.c.  defibrinated  blood  and  set  in  an 
incubator  at  40°  C.  Observe  in  fifteen  and  thirty  minutes.  Which 
tubes  can  you  read  printed  matter  through? 

Experiment  V. — Taste  a  0.1  per  cent,  solution  of  saponin.  Do  not 
swallow  more  than  1  c.c. 

Experiment  VI. — In  the  following  experiments  record  changes  in 
heart-rate,  respiration  and  general  symptoms.  Give  by  mouth  to 
a  dog  10  c.c.  of  0.1  per  cent,  solution  of  saponin  per  kilogram  body 
weight.    Note  and  record  symptoms. 

Experiment  VII. — Give  a  dog  2  c.c.  per  kilo  of  0.1  per  cent,  solution 
of  saponin  hypodermically. 

Experiment  VIII. — Give  a  dog  1  c.c.  per  kilo  of  0.1  per  cent,  saponin 
intravenously. 

Experiment  IX. — Take  a  tracing  of  a  frog  or  turtle  heart  and  per- 
fuse or  irrigate  it  with  0.01  per  cent,  saponin  in  0.8  per  cent.  NaCl. 
Compare  result  with  digitalis. 

LIST  OF  STOCK  SOLUTIONS. 

These  solutions  are  kept  for  convenience  and  may  be  diluted  when 
needed.  They  should  be  made  up  in  0.8  per  cent.  NaCl  or  in  Ringer's 
solution. 

Adrenalin  hydrochloride  or  other  epinephrin  solution,  1  to  1000.  It  is  preferable 
to  purchase  this  in  tablet  form  of  such  strength  that  one  tablet  in  1  c.c.  will  make 
a  1  to  1000  solution. 

Aconitin,  0.1  per  cent.,  also  the  tincture. 

Alcohol,  various  solutions  .      .      .      .  1  to  80  per  cent. 

Amyl  nitrite 1  per  cent,  and  in  3  minim  and  5  minim  pearls. 

Atropin 0.1  and  1  per  cent. 

Acacia 6  per  cent,  freshly  made. 

Barium  chloride 0.  01,  0. 1,  1  per  cent. 

Caffein 0. 1,  0.5,  1,  2  per  cent. 

Caffein  citrate 0.1,  0.5,  1,  2  per  cent. 

Caffein  sodio-benzoate        ....  0. 1,  0. 5,  2  per  cent. 

Calcium  chloride 0.1,0.3,0.5,  1  per  cent. 

Carbolic  acid 0.5,  1,  5  per  cent. 


LIST  OF  STOCK  SOLUTIONS 


245 


Chloral  hydrate 
Chloroform   . 
Cocaine,  HCl      . 
Codeine  phosphate 
Curara     . 
Digitalis 


Ergot,  fluidextract,  dilute  as  needed. 

Ether 

Hyoscyamin 


Morphin  sulphate 
Nicotin    . 


;e  as 


Nitioglj-cerin 

Physostigniin    or    physostigmin    sali- 
cylate          

Pilocarpin  nitrate 

Potassium  chloride 

Potassium  bromide        ... 
Quinine,  HCl      .      .  .... 

Quinine  bisulphate 

Sodium  nitrate 

Sodium  sulphate 

Strj-chnin,  nitrate  or  sulphate 

Thebain 

Veratrin  .  


0. 1,  1,  2  per  cent. 
0.05,  0. 1,  0.5  per  cent. 
0.01,  0.2,  0.5,  1  per  cent. 
0.5,  1  per  cent. 

0.5,  1  per  cent.,  slightly  acidify  with  /g  HCl. 
0.0005,  0.001,  0.002,  0.1,  0.5  percent.,  also 
the  tincture. 

1,  2,  5  per  cent. 

1    per  cent,  of   the   hydrochloride     and   the 

hydrobromide,  also  the  tincture. 
0.3  per  cent,  make  up  as  needed. 
0.1,  1  per  cent,  with  a  little  «__  HCl  diluti 

needed. 
0 . 1  per  cent. 

0. 1  and  1  per  cent. 
0. 1,  1  per  cent. 
0.03,  0.1,  5  per  cent. 
0.03,  0.1,  5  per  cent. 
0.1,1  per  cent. 
0.1,1  per  cent. 
0.01,  0.05,  1  per  cent. 
1,  10  per  cent. 
0.01,  0. 1,  1  per  cent. 
0.5,1  per  cent. 
0.  05,  1  per  cent. 


INDEX. 


Abducent  nerves,  100 
Absorption,  85 

acceleration  of,  85 
drugs  acting  after,  91 
from  alimentary  tract,  85 
retardation  of,  85 
Accessory  nerves,  104 
Acetonitril,  164 

Hunt's  test  for,  164 
Acidosis,  233,  235 
Acids,  216 

hydrocyanic,  215 
Aconitin,  117 

bio-assay  of,  119 
main  actions  of,  117 
Squibb's  test  for,  119 
Acoustic  nerves,  101 
Adaptation,  58 

Administration  of  drugs,  method  of,  24 
Adrenalin,    standardizing   of,    method 

of,  115 
Affinity,  elective,  23 
Alcohol,  121 

action  of,  antiseptic,  90 
on  heart,  121 
on  pupil,  121 
on  reflexes,  121 
effect  of,  on  student,  123 
as  a  food,  92 

group  of  drugs,  action  of,  91 
reactif)n  of,  on  student,  123 
Alcohol-chloral  grouj)  of  drugs,  121 

action  of,  on  heart, 
121 
Ahmentary  tract,  action  of  drugs  on,  56 
Alkalies,  216 
AlkaUnity  of  blood,  233 
potential,  233 
Ammonium,  221 
Anesthesia,  29,  124 

chlon)fonn,  symptoms  of,  125 
closed  method  of,  132 
ether,  126 

and  chloroform,  124 
8ymi)toiiis  of,  124 
for    dogs,    cats,    rabbits,    guinea- 
pigs,  31 
local,  30 
morphin-ether,  32 


Anesthesia,  nitrous-oxide,  132 
specific  action  of,  133 
symptoms  of,  124 
tests  for,  31 
Anesthetic  action  of  cocain,  147 
Anesthetics,    action     of,     on     central 
nervous  system,  29 
chief  local,  57 

effects  of,  on  circulation,  129 
on  respiration,  129 
on  temperature,  129 
Animals,  care  of,  29 
Anodynes,  local,  57 
Antagonism,  163 
chemical,  163 
definition  of,  163 
physiological,  163 
Anthelmintics,  84 

classification  of,  84 
Antidiuretics,  182 
Antipyi'esis,  173 
Antipyretics,  173,  174 
Antisepsis,  200 

intestinal,  87,  89 
Antiseptic  action  of  alcohol,  90 

dusting  powders,  89 
]  Antiseptics,  88 
Areas  of  brain,  motor,  93 

exposure  of,  93 
I  influence  of  drugs  on,  93 

Aromatic  bitters,  71 
Astringent  bitters,  72 
Astringents,  81 
I  classification  of,  82 

I  Atropin,  actions  of,  152 

on  third  nerve,  161 
Atropin-pilocarpin  group,  152 
Autonomic  drugs,  149,  152 

system,  classification  of,  149 
drugs  acting  on,  152 


B 


Bakium  salts,  211 

Benedict's  method  of  determining   vis- 
cosity of  sugar  ill  blood,  242 
Bernard's  experiment,  138 

"sugar  puncture,"  222 
Bitters,  71 

ad  ion  of,  72 


248 


INDEX 


Bitters,  aromatic,  71 
astringent,  72 
compound,  72 
local  action  of,  72 
principle,  71 
therapeutic  use  of,  73 
Bladder,  pharmacology  of,  200 
Blood,  alkahnity  of,  233 
clotting  of,  230 

agents  hastening,  232 
theories  of,  231 
corpuscles,  fragiHty  of,  238 

permeability  of  red,  240 
function  of,  222 
laking  of,  235 

agents  causing,  236 
pharmacology  of,  227 
specific  gravity  of,  235 
sugar   in,    Benedict's    method    of 

determining  viscosity  of,  242 
volume  of,  228 
Blood-pressure,    factors    concerned   in 
maintenance  of,  106 
methods  of  increasing,  107 

of  lowering,  107 
pharmacology  of,  106 
recording  of,  51 
Bloodvessels,  action  of  nitrites  on,  119 
Brain,  areas  of,  motor,  93 

exposure  of,  93 
influence  of  drugs  on,  93 
Bromides,  133 

actions  of,  133 

on  central  nervous  system,  133 
Burns,  treatment  of,  66 


Caffein,  183 

action    of,     on    central    nervous 
system,  183 
on  frog,  185 
on  heart,  184 
on  kidneys,  184 
mechanism  of,  184 
on  respiration,  184 
Calcium  salts,  211 
Cannabis,  134 

action    of,     on    central    nervous 

system,  135 
assay  of,  135 
preparation  of,  136 
standard  of,  136 
Carbon  dioxide,  242 
Carminatives,  74 
Cathartics,  78 

classification  of,  78 
therapeutic,  79 
definition  of,  78 
Caustic  poisoning,  70 

symptoms  of,  70 
treatment  of,  70 
Caustics,  69 


Central    nervous    system,    action    of 
anesthetics  on,  29 
of  bromides  on,  133 
of  caffein  on,  183 
of  cannabis  on,  135 
of  curara  on,  137 
of  morpliin  on,  32 
of  picrotoxin  on,  137 
of  strychnin  on,  137 
Cerebrum.     See  Central  nervous  sys- 
tem. 
Chloral-alcohol  group  of  drugs,  121 
Chloroform,  124 

anesthesia,  symptoms  of,  125 
CiUary  muscle,  action  of,  161 
Circulation,  action  of  nitrites  on,  118 

effects  of  anesthetics  on,  129 
Clotting  of  blood,  230 

agents  hastening,  232 
theories  of,  231 
Cocain,  local  anesthetic  action  of,  147 
Concentration  hydrogen  ion,  233 
Corpuscles,  fragiHty  of,  238 
permeabiUty  of  red,  240 
Corrosives,  216 

Curara,  action  of,  on  central  nervous 
system,  137 
on  mammals,  143 
on  motor  nerve  endings,  143 
Cyanhemoglobin,  239 


Demulcents,  62 
Digestants,  225 
Digitalis,  108 

standardization  of,  one  hour  frog 

method,  178 
standardizing  of,  gold  fish  method, 
115 
Hatcher's  cat  method,  114 
Digitaloid  drugs,  action  of,  109 
Diuresis,  theories  of,  181,  183 
Diuretics,  action  of,  182 
method  of,  187 
chief,  182 
saUne,  187 
Doses,  23 

Drugs,  administration  of,  methods  of, 
24,44 
definition  of,  17 
doses  of,  rules  for,  23 
fate  of,  in  body,  25 
Dusting  powders,  64 
antiseptic,  89 
essentials  of,  65 
principal,  64 


Emetics,  77 
irritant,  67 


INDEX 


249 


Emollients,  principal,  63 

use  of,  63 
Enzymes,  199,  225 

of  intestinal  juice,  180 
Epinephrin,  166 

action  of,  diflfering  from  ergotoxin, 
196 
Ergot,  193 

standardization  of,  198 
Ergotoxin,    action    of,    differing    from 

epinephrin,  196 
Escharotics,  67 

Eserin,  action  of,  differing  from  pilo- 
carpin,  162 
proof  of,  160 
Ether,  29,  124 

anesthesia,  126 

symptoms  of,  124 
Ether-morphin,  32 
Eye,  function  of,  160 

pharmacology  of,  160 


Facial  nerves,  100 

pharmacology  of,  101 
Fatigue,  causes  of,  19 
Ferments,  225 
Fluorides,  218 


G 


Gastric  glands,  179 
Gastro-intestinal  sedatives,  71 
tract,  71 

movements  of,  71,  86 
mechanism  of,  86 
pharmacology  of,  71 
Glands,  classification  of,  178 
drugs  affecting,  178 
function  of,  178 
gastric,  179 
intestinal,  179 

mammary,  i)harmacology  of,   194 
pharmacology  of,  178 
salivary,  179 
sweat,  191 

distribution  of,  191 
function  of,  191 
innervation  of,  191 
j)harmacology  of,  191 
Giossopharyngeai  nerves,  101 
Glycogen  in  liver,  193 
(ilycf)<uria,  exixu-imental,  222 
Gold    fish     riKithod    of    standardizing 
digitals,  115 


H 


Hatchku'h  cat  method  of  standardiz- 
ing digitalis,  114 


Heart,  action  of  alcohol  on,  121 
caffein  on,  184 
pharmacology  of,  106 
strychnin  on,  139 
drugs  depressing,  106 
stimulating,  106 

Heat  center,  174,  176 

Hematoporphyrin,  239 

Hemoglobin,  236,  237 

Hemolysis,  235 

Hermer's  test,  240 

Hunt's  test  for  acetonitril,  164 

Hydrocyanic  acid,  215 

Hypoglossal  nerves,  104 


Idiosyncrasy,  23 
Insufflation,  intratracheal,  32 

pharyngeal,  34 
Intestinal  antisepsis,  87,  89 

glands,  179 

juice,  enzymes  of,  180 
Intratracheal  insufflation,  32 
Involuntary  muscles,  202 

nervous  system,  149 
Iodides,  218 
Iris,  action  of,  161 
Irritant  emetics,  67 
Irritants,  local,  65 


Kidneys,  action  of  caffein  on,  184 
eUmination  of  drags  by,  183 
pharmacology  of,  181 


Laboratory  equipment,  26 

Lacrimal  glands,  drugs  acting  on,  160 

nerves  of,  160 
Lactagogues,  195 
Laking  of  lilood,  235 

agents  causing,  236 
Life,  chemical  essentials  of,  22 
Liver,    carbohydrate    metabolism    of, 
drugs  influencing,  194 

function  of,  193 

glycogen  in,  193 

pharmacology  of,  193 
Loches'  solution,  28 
Loop  M(jrea,n  method,  80 
Lympliagogucs,  213 
Lymi)hatics,  pharmticology  of,  213 


M 

MAfiNKKIUM  SJllls,  21  1 

Mammals,  ac^lion  of  curara  on,  143 


250 


INDEX 


Mammary   glands,    pharmacology    of, 

194 
Marshall  Hall  method  of  resuscitation, 

39 
Materia  medica,  definition  of,  18 
Meltzer  method  of  resuscitation,  35 
Metals,  heavy,  219 
Morphin,  action  of,  on  central  nervous 

system,  32 
Morphin-ether  anesthesia,  32 
Motor  nerve  endings,  action  of  curara 
on,  143 
paralysis  of,  143 
Mucous  membrane,  action  of  drugs  on, 

56 
Muscles,  classification  of,  201,  202 
drugs  acting  on,  203 

classification  of,  203 
involuntary,  202 
pharmacology  of,  201 
voluntary,  201 


N 


Nerve  endings,  motor,  action  of  curara 
on,  143 
paralysis  of,  143 
Nerve  fibers,  action  of  drugs  on,  146 
Nerves,  blocking  of,  60 
cranial,  96 

pharmacology  of,  96 
exposure  of,  47 
stimulation  of,  47 
Nervous  system,  involuntary,  149 
Nicotine,  action  of,  site  of,  157 

in  tobacco  smoke,  159 
Nitrites,  118,  208 
action  of,  208 

on  bloodvessels,  1 19 
on  circulation,  118 
on  respiration,  118 
Nitrous-oxide  anesthesia,  132 
specific  action  of,  133 


Obstipants,  81 

classification  of,  82 
Oculomotor  nerves,  99 

pharmacology  of,  100,  161 
Odors,  chemistry  and  physics  of,  97 

classification  of,  96 
Oils,  volatile,  74 

action  of,  74 

therapeutic  uses  of,  76 
Olfactory  nerves,  96 

drugs  acting  on,  98 
Optic  nerve,  98 

drugs  acting  on,  98 
Oxalates,  218 


Pancreas,  secretion  of,  179 
Paralysis,  20 

of  motor  nerve  endings,  143 
Parasympathetic  system,  149 
Pharmacodynamics,  definition  of,  18 
Pharmacognosy,  definition  of,  18 
Pharmacology,  affect  of,  25 

definition  of,  17 

subdivisions  of,  17 
Pharmacy,  definition  of,  18 
Pharyngeal  insufflation,  34 
Phenolsulphonephthalein,  189 

test  for,  190 
Phloridzih,  242 
Picrotoxin,     action     of,     on     central 

nervous  system,  137 
Pilocarpine,  action   of,    differing   from 
eserin,  162 
proof  of,  162 
Pilocarpine-atropin  group  of  drugs,  151 
Piqure,  222 
Pituitary  extract,  204 

standardization  of,  207 
Pituitrin,  203 
Poisoning,  caustic,  70 

sjonptoms  of,  70 
treatment  of,  70 
Poisons,  definition  of,  18 

general,  20 

special  or  selective,  21 
Potassium  salts,  220 
Poulsson's  experiment,  138 
Powders,  dusting,  64 
Pupil,  action  of  alcohol  on,  121 
Purgatives,  78 

classification  of,  78 
therapeutic,  79 

definition  of,  78 
Pustulants,  65 


Quinine,  209 


R 


Reflexes,  action  of  alcohol  on,  121 
alcohol-chloral  group  on,  121 
crossed,  122 
Respiration,  action  of  nitrites  on,  118 
caffein  on,  184 
strychnin  on,  139 
effects  of  anesthetics  on,  129 
recording  of,  52 
Resuscitation,   Marshall  Hall  method 
of,  37 
Meltzer  method  of,  35 
Schafer  method  of,  37 
Sylvester  method  of,  39 
Third  commission  on,  39 


INDEX 


251 


Resuscitation,    third    commission    on, 

resolutions  adopted  by,  41 
Retina,  drugs  depressing,  160 

stimulating,  160 
Ringer's  solution,  28 
Riminis  test,  241 
Rubefacients,  65 


Saline  diuretics,  187 

solution,  28 
Salivary  glands,  179 
Saponins,  243 
Scalds,  treatment  of,  66 
Schafer  method  of  resuscitation,  37 
Sedatives,  gastro-intestinal,  71 
Sensations,  classification  of,  92,  93 
Senses,  punctiform  distribution  of,  58 
Skin,  action  of  drugs  on,  56 

function  of,  55 
Spinal  animal,  preparation  of,  method 

of,  46 
Squibb's  test  for  aconitin,  119 
Stock  solutions,  Ust  of,  244 
Strychnin,  action  of,  on  central  nervous 
system,  137 

on  heart,  139 

on  respiration,  139 
Sugar  in  blood,  242 
Sulphides,  217 
Sweat  glands,  191 

distribution  of,  191 

function  of,  191 

innervation  of,  191 

pharmacology  of,  191 
Sylvester  method  of  resuscitation,  39 
Sympathetic  system,  149 
Synergism,  23,  164 

of  cocain  and  strychnin,  140 


Taste,  chemistry  of,  104 

definition  of,  96 
Temperature,  effects  of  anesthetics  on, 

129 
Therapeutics,  definition  of,  18 
Third  resuscitation  commission,  39 

resolution  adopted  by,  41 
Threshold,  absolute,  59 

differential,  59 
Tissues,  care  of,  29 
Tobacco  smoke,  nicotine  in,  159 
Toxicology,  definition  of,  18 
Trochlear  nerves,  pharmacology  of,  100 
Tyrode's  solution,  28 


U 


Urinary  secretion,  theory  of,  183 
Urine,  secretions  of,  factors  modifjang, 

181 
Uterus,  pharmacology  of,  195 


Vagus  nerve,  pharmacology  of,  104 
Ventricle,     fourth,     injecting     into, 

method  of,  46 
Veratrine,  action  of,  208 
Vesicants,  principal,  65 
Volatile  oils,  74 

action  of,  74 
therapeutic  uses  of,  76 
Voluntary  muscles,  201 


Young's  rule,  23 


Date  Due 

^'-^^^jl. 

— — ^^^^^^^— 1 

-^r^6^\: 

OCT  "?^  11 

840 

i 

' 

(|) 

